APOE
Apolipoprotein E precursor (Apo-E)
Publications[править]
Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic-risk-scores (PRS) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N=343), a population-matched cohort of older-adults from five cohorts (N=2905), and summary statistics data from a GWAS on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older-adults. This PRS was also associated with longer survival in an independent sample of younger individuals, (p=0.02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human lifespan is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.
Keywords
- centenarians
- cognitive health
- genetics
- healthy aging
- longevity
The Long Life Family Study (LLFS) is a family based, prospective study of healthy aging and familial longevity. The study includes two assessments of cognitive function that were administered approximately 8 years apart. To test whether APOE genotype is associated with change of cognitive function in older adults. We used Bayesian hierarchical models to test the association between APOE alleles and change of cognitive function. Six longitudinally collected neuropsychological test scores were modelled as a function of age at enrollment, follow-up time, gender, education, field center, birth cohort indicator (≤1935, or >1935), and the number of copies of ɛ2 or ɛ4 alleles. Out of 4,587 eligible participants, 2,064 were male (45.0%), and age at enrollment ranged from 25 to 110 years, with mean of 70.85 years (SD: 15.75). We detected a significant cross-sectional effect of the APOEɛ4 allele on Logical Memory. Participants carrying at least one copy of the ɛ4 allele had lower scores in both immediate (-0.31 points, 95% CI: -0.57, -0.05) and delayed (-0.37 points, 95% CI: -0.64, -0.10) recall comparing to non-ɛ4 allele carriers. We did not detect any significant longitudinal effect of the ɛ4 allele. There was no cross-sectional or longitudinal effect of the ɛ2 allele. The APOEɛ4 allele was identified as a risk factor for poorer episodic memory in older adults, while the APOEɛ2 allele was not significantly associated with any of the cognitive test scores.
Keywords
- APOE
- cognition
- longevity
- longitudinal studies
Little is known of gene-environment interactions for Alzheimer's disease (AD) risk factors. Apolipoprotein E (APOE) and neighbors on chromosome 19q13.3 have variants associated with risks of AD, but with unknown mechanism. This study describes novel links among the APOE network, air pollution, and age-related diseases. Mice exposed to air pollution nano-sized particulate matter (nPM) had coordinate responses of Apoe-Apoc1-Tomm40 in the cerebral cortex. In humans, the AD vulnerable hippocampus and amygdala had stronger age decline in APOE cluster expression than the AD-resistant cerebellum and hypothalamus. Using consensus weighted gene co-expression network, we showed that APOE has a conserved co-expressed network in rodent and primate brains. SOX1, which has AD-associated single nucleotide polymorphisms, was among the co-expressed genes in the human hippocampus. Humans and mice shared 87% of potential binding sites for transcription factors in APOE cluster promoter, suggesting similar inducibility and a novel link among environment, APOE cluster, and risk of AD.
Keywords
- Alzheimer's disease
- aging
- air pollution
- apolipoprotein E
- chromosome 19q13
Depressive symptoms are common comorbidities in schizophrenia. However, the effect of APOE E3 on depressive symptoms has never been investigated in an aging Chinese population with schizophrenia. This cross-sectional study aimed to investigate the effects of APOE E3 on blood lipid metabolism and depressive symptoms in elderly schizophrenics in China. Three Hundred and one elderly schizophrenics (161 males, age ranges from 60 to 92 years, with an average age of 67.31 ± 6.667) were included in the study. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). APOE gene polymorphism was determined by polymerase chain reaction (PCR). We assessed the correlations of GDS and serum low-density lipoprotein (LDL) with APOE genotypes. The concentration of LDL in the Homozygous APOE E3 group was significantly higher than that in the non-homozygous APOE E3 group, while the scores of GDS of the Homozygous APOE E3 group were lower than that in the non-homozygous APOE E3 group. Using partial correlation analysis and controlling age, gender, duration of disease, and hyperlipidemia, we found that the scores of GDS were significantly correlated with LDL ([i]r[/i] = -0.194, [i]p[/i] = 0.016). APOE E3 is associated with less depressive symptoms and higher serum LDL in Chinese elderly patients with schizophrenia, and there is a negative correlation between depressive symptoms and LDL.
Keywords
- APOE E3
- Chinese
- aging
- depressive symptom
- schizophrenia
Polymorphisms in the apolipoprotein E (APOE) gene have been associated with individual differences in cognition, brain structure and brain function. For example, the ε4 allele has been associated with cognitive and brain impairment in old age and increased risk of dementia, while the ε2 allele has been claimed to be neuroprotective. According to the 'antagonistic pleiotropy' hypothesis, these polymorphisms have different effects across the lifespan, with ε4, for example, postulated to confer benefits on cognitive and brain functions earlier in life. In this stage 2 of the Registered Report - https://osf.io/bufc4, we report the results from the cognitive and brain measures in the Cambridge Centre for Ageing and Neuroscience cohort (www.cam-can.org). We investigated the antagonistic pleiotropy hypothesis by testing for allele-by-age interactions in approximately 600 people across the adult lifespan (18-88 years), on six outcome variables related to cognition, brain structure and brain function (namely, fluid intelligence, verbal memory, hippocampal grey-matter volume, mean diffusion within white matter and resting-state connectivity measured by both functional magnetic resonance imaging and magnetoencephalography). We found no evidence to support the antagonistic pleiotropy hypothesis. Indeed, Bayes factors supported the null hypothesis in all cases, except for the (linear) interaction between age and possession of the ε4 allele on fluid intelligence, for which the evidence for faster decline in older ages was ambiguous. Overall, these pre-registered analyses question the antagonistic pleiotropy of APOE polymorphisms, at least in healthy adults.
Keywords
- Cognition
- ageing
- apolipoprotein E
- brain
- lifespan
Prior research investigating associations between hypertension, obesity, and apolipoprotein (APOE) genotype status with memory performance among older adults has yielded inconsistent results. This may reflect, in part, a lack of first accounting for the effects these variables have on structural brain changes, that in turn contribute to age-related memory impairment. The current study sought to clarify the relationships between these factors via path modeling. We hypothesized that higher body mass index (BMI), hypertension, and being an APOE-ε4 allele carrier would predict poorer memory scores, with much of these effects accounted for by indirect effects operating via differences in the integrity of temporal stem white matter. Participants included 125 healthy older adults who underwent neuropsychological assessment and diffusion-weighted MRI scanning. Direct effects were found for hypertension and demographic variables including age, sex, and education. Importantly, indirect effects were found for BMI, hypertension, APOE-ε4 status, age, and sex, where these factors predicted memory scores via their impact on temporal stem diffusion measures. There was also a dual effect of sex, with a direct effect indicating that females had better memory performance overall, and an indirect effect indicating that females with greater temporal stem diffusion had poorer memory performance. Results suggest that changes to the integrity of temporal white matter in aging may underpin reduced memory performance. These results highlight that accounting for variables that not only directly impact cognition, but also for those that indirectly impact cognition via structural brain changes, is crucial for understanding the impact of risk factors on cognition.
Keywords
- APOE
- BMI
- RRID:SCR_001398
- RRID:SCR_002403
- RRID:SCR_002823
- RRID:SCR_002865
- RRID:SCR_007037
- aging
- diffusion tensor imaging
- hypertension
- memory
- path modeling
Numerous neuroimaging studies demonstrated an association between the apolipoprotein E (APOE) [i]ε[/i]4 allele and resting-state functional connectivity (rsFC) of regions within the default mode network (DMN), both in healthy populations and patients with AD. It remains unclear whether the APOE [i]ε[/i]4 allele differentially affects the brain's functional network architecture across race/ethnicity. We investigated rsFC within DMN subsystems in 170 APOE [i]ε[/i]4 carriers compared to 387 APOE [i]ε[/i]4 non-carriers across three major racial/ethnic groups, including non-Hispanic Whites (n = 166), non-Hispanic Blacks (n = 185), and Hispanics (n = 206) from the Washington Heights-Inwood Columbia Aging Project. Compared to APOE [i]ε[/i]4 non-carriers, APOE [i]ε[/i]4 carriers had lower rsFC in temporal DMN, but only in non-Hispanic Whites. Non-Hispanic Black and Hispanic APOE [i]ε[/i]4 carriers had slightly higher or similar rsFC compared with non-Hispanic White APOE [i]ε[/i]4 non-carriers. These findings suggest that APOE [i]ε[/i]4 modulates DMN rsFC differently in non-Hispanic Whites compared with non-Hispanic Blacks and Hispanics.
Keywords
- APOE ε4 differences
- brain aging
- dementia
- neuroimaging
- racial/ethnic differences
- resting‐state functional connectivity
It is critical to identify individuals at risk for Alzheimer's disease (AD) earlier in the disease time course, such as middle age and preferably well prior to the onset of clinical symptoms, when intervention efforts may be more successful. Genome-wide association and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in APOE, CLU, CR1, PICALM, and SORL1 that confer increased risk of AD. In the current study, we investigated the associations between SNPs in these genes and resting-state functional connectivity within the default mode network (DMN), frontoparietal network (FPN), and executive control network (ECN) in healthy, non-demented middle-aged adults (age 40 -60; N = 123; 74 females). Resting state networks of interest were identified through independent components analysis using a template-matching procedure and individual spatial maps and time courses were extracted using dual regression. Within the posterior DMN, functional connectivity was associated with CR1 rs1408077 and CLU rs9331888 polymorphisms (p's < 0.05). FPN connectivity was associated with CR1 rs1408077, CLU rs1136000, SORL1 rs641120, and SORL1 rs689021 (p's < 0.05). Functional connectivity within the ECN was associated with the CLU rs11136000 (p < 0.05). There were no APOE- or PICALM-related differences in any of the networks investigated (p's > 0.05). This is the first demonstration of the relationship between intrinsic network connectivity and AD risk alleles in CLU, CR1, and SORL1 in healthy, middle-aged adults. These SNPs should be considered in future investigations aimed at identifying potential preclinical biomarkers for AD.
Keywords
- Aging
- Alzheimer’s disease
- middle aged
- neuroimaging
- single nucleotide
polymorphism
The cognitive trajectories in normal aging may be affected by medial temporal atrophy (MTA) and amyloid burden, as well as vascular pathologies such as cortical microbleeds (CMB) and white matter hyperintensities (WMH). We addressed here the role of imaging markers in their prediction in a real-world situation. We performed a 4.5-year longitudinal study in 90 older community-dwellers coupling two neuropsychological assessments, MTA estimated with the Schelten's scale, number of CMB, and WMH evaluated with the Fazekas score at inclusion and follow-up, visual rating of amyloid PET and glucose hypometabolism at follow-up, and APOE genotyping. Regression models were built to explore the association between the continuous cognitive score (CCS) and imaging parameters. The number of strictly lobar CMB at baseline (4 or more) was related to a 5.5-fold increase of the risk of cognitive decrement. This association persisted in multivariable models explaining 10.6% of the CCS decrease variance. MTA, and Fazekas score at baseline and amyloid positivity or abnormal FDG PET, were not related to the cognitive outcome. The increase of right MTA at follow-up was the only correlate of CCS decrease both in univariate and multivariable models explaining 9.2% of its variance. The present data show that the accumulation of more than four CMB is associated with significant cognitive decrement over time in highly educated elderly persons. They also reveal that the progressive deterioration of cognitive performance within the age-adjusted norms is also related to the increase of visually assessed MTA.
Keywords
- Atrophy
- cognition
- imaging markers
- medial temporal lobe
- microbleeds
- normal aging
Cardiovascular disease (CVD) is one of the most important causes of human death, but no attention has been paid to cardiovascular health genes related to healthy longevity. Therefore, we developed a cohort study to explore such genes in healthy, long-lived Chinese subjects. A total of 13275 healthy elderly people were enrolled, including 5107 healthy long-lived individuals and 8168 age-matched control individuals with low CVD risk. Using a combination of whole-exome sequencing (WES) and genome-wide association studies (GWAS), we identified 2 genetic variants (TFPI rs7586970 T, p=0.013, OR=1.100. ADAMTS7 rs3825807 A, p=0.017, OR=1.198) associated with healthy lipid metabolism and longevity. Furthermore, we showed that an interaction among TFPI rs7586970, ADAMTS7 rs3825807 and APOE ɛ3 maintained normal blood lipid levels in centenarians by stratified analysis of CVD risk factors. Finally, through biological function analysis, we revealed clues regarding the mechanism of factor related to cardiovascular health (FCH) such as lipids and longevity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the two variants above may be associated with longevity via FCH lipid metabolism pathways. From a meta-analysis of venous thrombosis patients, we unexpectedly found that rs7586970 T is associated with both longevity and protection against vascular disease.
Keywords
- Chinese
- factor related to cardiovascular health (FCH)
- genetic variation
- lipid metabolism
- longevity
Olfactory dysfunction is common in aging and associated with dementia and mortality. However, longitudinal studies tracking change in olfactory ability are scarce. We sought to identify predictors of interindividual differences in rate of olfactory identification change in aging. Participants were 1780 individuals, without dementia at baseline and with at least 2 olfactory assessments over 12 years of follow-up (mean age = 70.5 years; 61.9% female), from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Odor identification was assessed with the Sniffin' Sticks. We estimated the impact of demographic, health, and genetic factors on rate of olfactory change with linear mixed effect models. Advancing age, manufacturing profession, history of cerebrovascular disease, higher cardiovascular disease burden, diabetes, slower walking speed, higher number of medications, and the APOE ε4 allele were associated with accelerated odor identification decline (ps < .014). Multi-adjusted analyses showed unique associations of age, diabetes, and ε4 to olfactory decline (ps < .017). In 1531 participants who remained free of dementia (DSM IV criteria) during follow-up, age, cardiovascular disease burden, and diabetes were associated with accelerated decline (ps < .011). Of these, age and diabetes remained statistically significant in the multi-adjusted model (ps < .001). Demographic, vascular, and genetic factors are linked to rate of decline in odor identification in aging. Although some olfactory loss may be an inevitable part of aging, our results highlight the importance of vascular factors for the integrity of the olfactory system, even in the absence of dementia.
Keywords
- Cognitive aging
- Epidemiology
- Olfactory
- Olfactory impairment
Most studies of aging cognition have focused on risk factors for worse performance and on either genetic or environmental factors. In contrast, we examined whether 2 factors known to individually benefit aging cognition may interact to produce better cognition: environment-based positive age beliefs and the APOE ε2 gene. The sample consisted of 3,895 Health and Retirement Study participants who were 60 years or older at baseline and completed as many as 5 assessments of cognition over 8 years. As predicted, positive age beliefs amplified the cognitive benefit of APOE ε2. In contrast, negative age beliefs suppressed the cognitive benefit of APOE ε2. We also found that positive age beliefs contributed nearly 15 times more than APOE ε2 to better cognition. This study provides the first known evidence that self-perceptions can influence the impact of a gene on cognition. The results underscore the importance of combined psychosocial and biological approaches to understanding cognitive function in older adults.
Keywords
APOE
- Age beliefs
- Cognition
- Gene
- Health and Retirement Study
- Self-perceptions of aging
The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Apolipoprotein E4
- Biomarkers
- Case-Control Studies
- Cohort Studies
- Female
- Genotype
- Humans
- Male
- Middle Aged
Preventing dementia onset is one of the global public health priorities: around 35% of dementia cases could be attributable to modifiable risk factors. These estimates relied on secondary data and did not consider the concurrent effect of non-modifiable factors and death. Here, we aimed to estimate the potential reduction of dementia incidence due to modifiable risk factors elimination, controlling for non-modifiable risk factors and for the competing risk of death. Participants from the InveCe.Ab population-based prospective cohort (Abbiategrasso, Italy) without a baseline dementia diagnosis and attending at least one follow-up visit were included (N = 1100). Participants underwent multidimensional assessment at baseline and after 2, 4, and 8 years, from November 2009 to January 2019. Modifiable risk factors were low education, obesity, hypertension, diabetes, depression, smoking, physical inactivity, hearing loss, loneliness, heart disease, stroke, head injury, and delirium. Non-modifiable risk factors were age, sex, and APOE ε4 genotype. The primary endpoint was dementia diagnosis within the follow-up period (DSM-IV criteria). We performed competing risk regression models to obtain sub-hazard ratio (SHR) for each exposure, with death as competing risk. The exposures associated with dementia were included in a multivariable model to estimate their independent influence on dementia and the corresponding population attributable fraction (PAF). Within the study period (mean follow-up, 82.3 months), 111 participants developed dementia (10.1%). In the multivariable model, APOE ε4 (SHR = 1.89, 95% CI 1.22-2.92, p = 0.005), diabetes (SHR = 1.56, 95% CI 1.00-2.39, p = 0.043), heart disease (SHR = 1.56, 95% CI 1.03-2.36, p = 0.037), stroke (SHR = 2.31, 95% CI 1.35-3.95, p = 0.002), and delirium (SHR = 8.70, 95% CI 3.26-23.24, p < 0.001) were independently associated with increased dementia risk. In the present cohort, around 40% of dementia cases could be attributable to preventable comorbid diseases. APOE ε4, diabetes, heart disease, stroke, and delirium independently increased the risk of late-life dementia, controlling for the competing risk of death. Preventive intervention addressed to these clinical populations could be an effective approach to reduce dementia incidence. Further studies on different population-based cohort are needed to obtain more generalizable findings of the potential of dementia prevention in the real-world setting. ClinicalTrials.gov, NCT01345110 .
Keywords
- Aging
- Alzheimer’s disease
- Dementia
- Dementia prevention
- Modifiable risk factors
- Population attributable fraction
- Public health
High dimensional neuroimaging datasets and machine learning have been used to estimate and predict domain-specific cognition, but comparisons with simpler models composed of easy-to-measure variables are limited. Regularization methods in particular may help identify regions-of-interest related to domain-specific cognition. Using data from the Northern Manhattan Study, a cohort study of mostly Hispanic older adults, we compared three models estimating domain-specific cognitive performance: sociodemographics and APOE ε4 allele status (basic model), the basic model and MRI markers, and a model with only MRI markers. We used several machine learning methods to fit our regression models: elastic net, support vector regression, random forest, and principal components regression. Model performance was assessed with the RMSE, MAE, and R statistics using 5-fold cross-validation. To assess whether prediction models with imaging biomarkers were more predictive than prediction models built with randomly generated biomarkers, we refit the elastic net models using 1000 datasets with random biomarkers and compared the distribution of the RMSE and R in models using these random biomarkers to the RMSE and R from observed models. Basic models explained ~ 31-38% of the variance in domain-specific cognition. Addition of MRI markers did not improve estimation. However, elastic net models with only MRI markers performed significantly better than random MRI markers (one-sided P < .05) and yielded regions-of-interest consistent with previous literature and others not previously explored. Therefore, structural brain MRI markers may be more useful for etiological than predictive modeling.
Keywords
- Biomarkers
- Brain aging
- Cognitive aging
- Machine learning
APOE-ε4 is a major genetic risk factor for late-onset Alzheimer's disease that interacts with other risk factors, but the nature of such combined effects remains poorly understood. We quantified the impact of APOE-ε4, family history (FH) of dementia, and obesity on white matter (WM) microstructure in 165 asymptomatic adults (38-71 years old) using quantitative magnetization transfer and neurite orientation dispersion and density imaging. Microstructural properties of the fornix, parahippocampal cingulum, and uncinate fasciculus were compared with those in motor and whole-brain WM regions. Widespread interaction effects between APOE, FH, and waist-hip ratio were found in the myelin-sensitive macromolecular proton fraction from quantitative magnetization transfer. Among individuals with the highest genetic risk (FH and APOE-ε4), obesity was associated with reduced macromolecular proton fraction in the right parahippocampal cingulum, whereas no effects were present for those without FH. Risk effects on apparent myelin were moderated by hypertension and inflammation-related markers. These findings suggest that genetic risk modifies the impact of obesity on WM myelin consistent with neuroglia models of aging and late-onset Alzheimer's disease.
Keywords
- APOE
- Aging
- Alzheimer’s disease
- Central obesity
- Family history of dementia
- Hypertension
- Inflammation
- Myelin
- Parahippocampal cingulum
- The rs405509 polymorphism ofthe apolipoprotein E (APOE) promoter is related to Alzheimer'sdisease (AD). The T/T allele of rs405509 is known to decrease the transcription of the APOE gene and lead to impairments in specific brain structural networks with aging; thus, it is an important risk factor for AD. However, it remains unknown whether rs405509 affects brain functional connectivity (FC) in aging. : We investigated the effect of the rs405509 genotype (T/T vs. G-allele) on age-related brain FC using functional magnetic resonance imaging. Forty-five elderly TT carriers and 45 elderly G-allele carriers were scanned during a working memory (WM) task. : We found that TT carriers showed an accelerated age-related increase in functional activation in the left postcentral gyrus compared with G-allele carriers. Furthermore, the FC between the left postcentral gyrus and some key regions during WM performance, including the right caudal and superior frontal sulcus (SFS), was differentially modulated by age across rs405509 genotype groups. : These results demonstrate that the rs405509 T/T allele of APOE causes an age-related brain functional decline in nondemented elderly people, which may be beneficial for understanding the neural mechanisms of rs405509-related cognitive aging and AD pathogenesis.
Keywords
- APOE promoter
- aging
- brain connectome
- fronto-parietal network
- working memory
A few studies report that parental longevity is associated with preserved cognition and physical function and lower risk of Alzheimer's disease. However, data on structural neuroimaging correlates of parental longevity and its spatial distribution are limited. This study aims to examine relationships of parental longevity with regional brain structure and to explore sex differences. We identified 12,970 UK Biobank participants (mean age = 64.4, 51.5%women) with data on parental longevity, regional gray matter volumes, and white matter microstructure. Participants were categorized based on whether at least one parent lived to age 85 or older or neither parent survived to age 85. Associations of parental longevity, maternal, and paternal longevity with each neuroimaging marker of interest were examined using linear regression, adjusted for demographics, APOE e4 status, lifestyle, and cardiometabolic conditions. Compared to participants whose both parents died before 85 (43%), those with at least one parent surviving to 85 (57%) had greater volumes in hippocampus, parahippocampal gyrus, middle temporal lobe, and primary sensorimotor cortex and had lower mean diffusivity in posterior thalamic radiation and uncinate fasciculus. Associations were prominent with maternal longevity. Adjustment for cardiometabolic conditions did not affect observed associations except mean diffusivity in posterior thalamic radiation. There were no structural differences in other areas. Parental longevity is associated with preserved brain structure localized in primary sensorimotor cortex and temporal areas including hippocampus. These relationships are prominent with maternal longevity. Longitudinal studies are needed to determine whether changes in these brain structures account for the association between parental longevity and dementia.
Keywords
- Aging
- Brain structure
- DTI
- MRI
- Neuroimaging
- Parental longevity
Damage-associated microglia (DAM) profiles observed in Alzheimer's disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD microglia (HAM) display a similar profile, we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches. The HAM profile we observe bears little resemblance to the DAM profile. Instead, HAM display an enhanced human aging profile, in addition to other disease-related changes such as APOE upregulation. Analyses of whole-tissue RNA-seq and single-cell/nucleus RNA-seq datasets corroborate our findings and suggest that the lack of DAM response in human microglia occurs specifically in AD tissues, not other neurodegenerative settings. These results, which can be browsed at http://research-pub.gene.com/BrainMyeloidLandscape, provide a genome-wide picture of microglial activation in human AD and highlight considerable differences between mouse models and human disease.
Keywords
- Alzheimer’s disease
- aging
- microglia
- neurodegenerative diseases
- neuroinflammation
- transcriptomics
Maintaining good cognitive function at older age is important, but our knowledge of patterns and predictors of cognitive aging is still limited. We used Bayesian model-based clustering to group 5064 participants of the Long Life Family Study (ages 49-110 years) into clusters characterized by distinct trajectories of cognitive change in the domains of episodic memory, attention, processing speed, and verbal fluency. For each domain, we identified 4 or 5 large clusters with representative patterns of change ranging from rapid decline to exceptionally slow change. We annotated the clusters by their correlation with genetic and molecular biomarkers, non-genetic risk factors, medical history, and other markers of aging to discover correlates of cognitive changes and neuroprotection. The annotation analysis discovered both predictors of multi-domain cognitive change such as gait speed and predictors of domain-specific cognitive change such as IL6 and NTproBNP that correlate only with change of processing speed or APOE genotypes that correlate only with change of processing speed and logical memory. These patterns also suggest that cognitive decline starts at young age and that maintaining good physical function correlates with slower cognitive decline. To better understand the agreement of cognitive changes across multiple domains, we summarized the results of the cluster analysis into a score of cognitive function change. This score showed that extreme patterns of change affecting multiple cognitive domains simultaneously are rare in this study and that specific signatures of biomarkers of inflammation and metabolic disease predict severity of cognitive changes. The substantial heterogeneity of change patterns within and between cognitive domains and the net of correlations between patterns of cognitive aging and other aging traits emphasizes the importance of measuring a wide range of cognitive functions and the need for studying cognitive aging in concert with other aging traits.
Keywords
- Aging
- Biomarker
- Cognition
- Neuropsychology
Here, we perform a genome-wide screen for variants that regulate the expression of gene co-expression modules in the aging human brain; we discover and replicate such variants in the TMEM106B and RBFOX1 loci. The TMEM106B haplotype is known to influence the accumulation of TAR DNA-binding protein 43 kDa (TDP-43) proteinopathy, and the haplotype's large-scale transcriptomic effects include the dysregulation of lysosomal genes and alterations in synaptic gene splicing that are also seen in the pathophysiology of TDP-43 proteinopathy. Further, a variant near GRN, another TDP-43 proteinopathy susceptibility gene, shows concordant effects with the TMEM106B haplotype. Leveraging neuropathology data from the same participants, we also show that TMEM106B and APOE-amyloid-β effects converge to alter myelination and lysosomal gene expression, which then contributes to TDP-43 accumulation. These results advance our mechanistic understanding of the TMEM106B TDP-43 risk haplotype and uncover a transcriptional program that mediates the converging effects of APOE-amyloid-β and TMEM106B on TDP-43 aggregation in older adults.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Apolipoproteins E
- Brain
- Cohort Studies
- DNA-Binding Proteins
- Female
- Gene Expression Regulation
- Haplotypes
- Humans
- Lysosomes
- Male
- Membrane Proteins
- Myelin Sheath
- Nerve Tissue Proteins
- Progranulins
- Quantitative Trait Loci
- RNA Splicing Factors
- TDP-43 Proteinopathies
Keywords
- Alzheimer's disease
- Amyloid-β
- GRN
- RBFOX1
- TDP-43
- TMEM106B
- co-expression module
- cognitive resilience
- eQTL
- expression quantitative trait loci
- sQTL
- splicing quantitative trait loci
Lipid metabolism is altered in Alzheimer's disease (AD); however, the relationship between AD risk factors (age, APOEɛ4, and gender) and lipid metabolism is not well defined. We investigated whether altered lipid metabolism associated with increased age, gender, and APOE status may contribute to the development of AD by examining these risk factors in healthy controls and also clinically diagnosed AD individuals. We performed plasma lipidomic profiling (582 lipid species) of the Australian Imaging, Biomarkers and Lifestyle flagship study of aging cohort (AIBL) using liquid chromatography-mass spectrometry. Linear regression and interaction analysis were used to explore the relationship between risk factors and plasma lipid species. We observed strong associations between plasma lipid species with gender and increasing age in cognitively normal individuals. However, APOEɛ4 was relatively weakly associated with plasma lipid species. Interaction analysis identified differential associations of sphingolipids and polyunsaturated fatty acid esterified lipid species with AD based on age and gender, respectively. These data indicate that the risk associated with age, gender, and APOEɛ4 may, in part, be mediated by changes in lipid metabolism. This study extends our existing knowledge of the relationship between the lipidome and AD and highlights the complexity of the relationships between lipid metabolism and AD at different ages and between men and women. This has important implications for how we assess AD risk and also for potential therapeutic strategies involving modulation of lipid metabolic pathways.
Keywords
- APOEɛ4
- Aging
- Alzheimer’s disease
- gender
- lipid
species
Early detection of Alzheimer's disease (AD) is important for timely interventions and developing new treatments. Hippocampus atrophy is an early biomarker of AD. The hippocampal parenchymal fraction (HPF) is a promising measure of hippocampal structural integrity computed from structural MRI. It is important to characterize the dependence of HPF on covariates such as age and sex in the normal population to enhance its utility as a disease biomarker. We measured the HPF in 4239 structural MRI scans from 340 cognitively normal (CN) subjects aged 59-89 years from the AD Neuroimaging Initiative database, and studied its dependence on age, sex, apolipoprotein E (APOE) genotype, brain hemisphere, intracranial volume (ICV), and education using a linear mixed-effects model. In this CN cohort, HPF was inversely associated with ICV; was greater on the right hemisphere compared to left in both sexes with the degree of right > left asymmetry being slightly more pronounced in men; declined quadratically with age and faster in APOE ϵ4 carriers compared to non-carriers; and was significantly associated with cognitive ability. Consideration of HPF as an AD biomarker should be in conjunction with other subject attributes that are shown in this research to influence HPF levels in CN older individuals.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Apolipoproteins E
- Biomarkers
- Cognition
- Databases, Factual
- Female
- Genotype
- Hippocampus
- Humans
- Linear Models
- Male
- Middle Aged
- Neuroimaging
- Organ Size
- Parenchymal Tissue
- Reference Values
- Sex Factors
Keywords
- Alzheimer’s disease
- Apolipoprotein E ϵ4
- Atrophy
- Brain
- Healthy aging
- Hippocampal parenchymal fraction
- Hippocampal volumetric integrity
- Hippocampus
- MRI
- Mild cognitive impairment
- Neurodegeneration
- Sex
[i]Background[/i][i]:[/i] Nonagenarians and centenarians (NCs) are an extremely fragile population, particularly in regard to their physical and cognitive function. The aim of this study was to define the neurocognitive profiles among 29 NCs and their 49 younger cohabitants aged 50-75 years from The Cilento Initiative on Aging Outcomes (CIAO) Pilot study in the South of Italy that had provided initial hypotheses regarding positive psychological traits related to exceptional longevity. [i]Methods[/i]: During the home visits, lifestyle information with specific questionnaires, functional autonomy and the neuropsychological Mini Mental Scale Examination (MMSE), and the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) scale were obtained by qualified study personnel. The total blood oxidative capacity was also determined by testing the reactive derivative of oxygen metabolites (d-ROM) and by the Biological Antioxidant Potential (BAP). In all individuals, the APOE genotype determination was also performed. [i]Results[/i]: All the subjects in both groups showed high adherence to the Mediterranean Diet. None of the NCs had severe cognitive impairment, and a very low incidence of dementia was found. The data obtained on the Activities ed Instrumental Activities of Daily Living (ADL-IADL) scale showed that the majority of NCs (16/29) were autonomous in daily life activities. The comparative assessment of NCs and cohabitants showed no significant differences in the laboratory assessment of oxidative stress and APOE genotype. [i]Conclusion:[/i] In the Cilento Region of Southern Italy, NCs seemed to have good cognitive status when compared to younger cohabitants aging 50-65 years without significant differences in oxidative stress markers or APOE genotype. These results might be related to optimal adherence to the Mediterranean diet, although other lifestyle factors and positive personality traits may also contribute to their healthy aging. Further studies on a larger population should be performed to confirm the results of this pilot study.
Keywords
- Cilento Region
- cognitive health
- lifestyle
- longevity
APOE genotype has been associated with various age-related outcomes including Alzheimer's disease, frailty, and mortality. In this study, the relationship between health, particularly cognitive function, and APOE was investigated in older men from the Concord Health and Ageing in Men Project (n = 1,616; age 76.9 ± 5.5 years [range 70-97 years]; Australia). Baseline characteristics and survival up to 12 years were determined. Frailty was measured using Cardiovascular Health study (CHS) criteria and Rockwood frailty index, and cognition using Mini-Mental State Examination (MMSE) and Addenbrookes Cognitive Examination. APOE ε4 was less common in the oldest men and those born in Mediterranean countries. APOE ε2 was beneficially associated with cholesterol, creatinine, gamma-glutamyl transaminase, glucose, and HDL cholesterol while APOE ε4 was adversely associated with cholesterol and albumin. APOE ε4 was associated with a clinical diagnosis of Alzheimer's disease when adjusted for age and region of birth (ε4 homozygotes Odds ratio (OR) 7.0; ε4 heterozygotes OR 2.4, p < .05), and APOE ε2 had a small positive association with cognition. On multivariate regression, overall cognitive function in the entire cohort was associated with age, country of birth, education, and frailty (all p < .001). APOE was not associated with frailty or survival. In conclusion, age and region of birth influenced distribution of APOE genotype in older men. Although APOE ε4 was associated with Alzheimer's disease, overall cognitive function in the cohort was associated more strongly with frailty than APOE genotype.
Keywords
- Aging
- Alzheimer’s disease
- Apolipoprotein E
- Cognition
- Cognitive frailty
- Frailty
- Male
The hippocampus is one of the first regions to demonstrate atrophy during the prodromal stage of Alzheimer's disease. Volumetric analysis of its individual subfields could provide biomarkers with higher sensitivity than whole hippocampal volume during an earlier disease stage. We quantified the hippocampal subfields volume in a large cohort comprising healthy participants (aged 40-59) with dementia family history (FH) and controls (without FH), examined at 2 time points across 2 years. Subfield volumes were quantified using both a T1-weighted and a high-resolution T2 hippocampal magnetic resonance imaging acquisition with Freesurfer. The participants were stratified based on dementia FH, APOE genotype, and CAIDE (Cardiovascular Risk Factors, Aging and Dementia) risk score. Whole hippocampal volume did not differ between the groups. The volume of the molecular layer was lower in participants with an APOE ε4 genotype, but there were no differences between subjects with and without dementia FH or with an increasing CAIDE score. The molecular layer may be the first hippocampal region to demonstrate volumetric alterations in subjects at risk of dementia.
MeSH Terms
- Adult
- Aging
- Alzheimer Disease
- Apolipoproteins E
- Atrophy
- Dementia
- Diffusion Magnetic Resonance Imaging
- Educational Status
- Female
- Genotype
- Hippocampus
- Humans
- Male
- Middle Aged
- Organ Size
- Risk
Keywords
- Alzheimer's disease
- Dementia
- Hippocampal subfields
- Hippocampus
- Preclinical dementia
This study investigated the relationship between white matter hyperintensities (WMH) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. Subjects included 180 controls, 107 individuals with a significant memory concern, 320 individuals with early mild cognitive impairment, 171 individuals with late mild cognitive impairment, and 151 individuals with AD, with 3T MRI and CSF Aβ1-42, total tau (t-tau), and phosphorylated tau (p-tau) data. Multiple linear regression models assessed the relationship between WMH and CSF Aβ1-42, t-tau, and p-tau. Directionally, a higher WMH burden was associated with lower CSF Aβ1-42 within each diagnostic group, with no evidence for a difference in the slope of the association across diagnostic groups (p = 0.4). Pooling all participants, this association was statistically significant after adjustment for t-tau, p-tau, age, diagnostic group, and APOE-ε4 status (p < 0.001). Age was the strongest predictor of WMH (partial R ~16%) compared with CSF Aβ1-42 (partial R ~5%). There was no evidence for an association with WMH and either t-tau or p-tau. These data are supportive of a link between amyloid burden and presumed vascular pathology.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Biomarkers
- Cerebrovascular Disorders
- Cognitive Dysfunction
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Peptide Fragments
- White Matter
- tau Proteins
Keywords
- Alzheimer's disease
- Amyloid
- Cerebrospinal fluid
- Tau
- Vascular disease
- White matter hyperintensities
Midlife cardiovascular risk factors increase risk for Alzheimer's disease (AD). Despite disproportionately high cardiovascular disease and dementia rates, African Americans are under-represented in studies of AD risk and research-based guidance on targeting vascular risk factors is lacking. This study investigated relationships between specific cardiovascular risk factors and cerebral perfusion in White and African American adults enriched for AD risk. Participants included 397 cognitively unimpaired White (n = 330) and African American (n = 67) adults enrolled in the Wisconsin Alzheimer's Disease Research Center who underwent pseudo-continuous arterial spin labeling MRI. Multiple linear regression models examined independent relationships between cardiovascular risk factors and mean cerebral perfusion. Subsequent interaction and stratified models assessed the role for APOE genotype and race. When risk factor p-values were FDR-adjusted, diastolic blood pressure was significantly associated with mean perfusion. Tobacco use, triglycerides, waist-to-hip ratio, and a composite risk score were not associated with perfusion. Without FDR adjustment, a relationship was also observed between perfusion and obesity, cholesterol, and fasting glucose. Neither APOE genotype nor race moderated relationships between risk factors and perfusion. Higher diastolic blood pressure predicted lower perfusion more strongly than other cardiovascular risk factors. This relationship did not vary by racial group or genetic risk for AD, although the African American sample had greater vascular risk burden and lower perfusion rates. Our findings highlight the need to prioritize inclusion of underrepresented groups in neuroimaging studies and to continue exploring the link between modifiable risk factors, cerebrovascular health, and AD risk in underrepresented populations.
Keywords
- Aging
- Alzheimer’s disease
- blood pressure
- cerebrovascular circulation
- neuroimaging
- obesity
Evidence suggests interplay among the three major risk factors for Alzheimer's disease (AD): age, APOE genotype, and sex. Here, we present comprehensive datasets and analyses of brain transcriptomes and blood metabolomes from human apoE2-, apoE3-, and apoE4-targeted replacement mice across young, middle, and old ages with both sexes. We found that age had the greatest impact on brain transcriptomes highlighted by an immune module led by Trem2 and Tyrobp, whereas APOE4 was associated with upregulation of multiple Serpina3 genes. Importantly, these networks and gene expression changes were mostly conserved in human brains. Finally, we observed a significant interaction between age, APOE genotype, and sex on unfolded protein response pathway. In the periphery, APOE2 drove distinct blood metabolome profile highlighted by the upregulation of lipid metabolites. Our work identifies unique and interactive molecular pathways underlying AD risk factors providing valuable resources for discovery and validation research in model systems and humans.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Age Factors
- Aging
- Alzheimer Disease
- Animals
- Apolipoprotein E2
- Apolipoprotein E3
- Apolipoprotein E4
- Apolipoproteins E
- Brain
- Female
- Gene Expression
- Gene Expression Profiling
- Gene Regulatory Networks
- Genotype
- Humans
- Male
- Membrane Glycoproteins
- Membrane Proteins
- Metabolome
- Mice
- Mice, Transgenic
- Protective Factors
- Receptors, Immunologic
- Risk Factors
- Serpins
- Sex Factors
- Unfolded Protein Response
Keywords
- APOE
- Alzheimer’s disease
- Serpina3
- age
- extracellular vesicles
- inflammation
- lipid metabolism
- metabolomics
- sex
- transcriptomics
Brown adipose tissue (BAT) plays a critical role in lipid metabolism and may protect from hyperlipidemia; however, its beneficial effect appears to depend on the ambient temperature of the environment. In this study, we investigated the effects of uncoupling protein 1 (UCP1) deficiency on lipid metabolism, including the pathophysiology of hyperlipidemia, in apolipoprotein E knockout (APOE-KO) mice at a normal (23 °C) and thermoneutral (30 °C) temperature. Unexpectedly, UCP1 deficiency caused improvements in hyperlipidemia, atherosclerosis, and glucose metabolism, regardless of an increase in hepatic lipid deposition, in Ucp1/Apoe double-knockout (DKO) mice fed a high-fat diet at 23 °C, with BAT hyperplasia and robust browning of inguinal white adipose tissue (IWAT) observed. Proteomics and gene expression analyses revealed significant increases in many proteins involved in energy metabolism and strong upregulation of brown/beige adipocyte-related genes and fatty acid metabolism-related genes in browned IWAT, suggesting an induction of beige fat formation and stimulation of lipid metabolism in DKO mice at 23 °C. Conversely, mRNA levels of fatty acid oxidation-related genes decreased in the liver of DKO mice. The favorable phenotypic changes were lost at 30 °C, with BAT whitening and disappearance of IWAT browning, while fatty liver further deteriorated in DKO mice compared with that in APOE-KO mice. Finally, longevity analysis revealed a significant lifespan extension of DKO mice compared with that of APOE-KO mice at 23 °C. Irrespective of the fundamental role of UCP1 thermogenesis, our results highlight the importance of beige fat for the improvement of hyperlipidemia and longevity under the atherogenic status at normal room temperature.
Keywords
- Apoe knockout mice
- Beige fat
- Gene expression
- Hyperlipidemia
- Longevity
- Uncoupling protein 1
The relationship between personality profiles and brain integrity in old age is still a matter of debate. We examined the association between Big Five factor and facet scores and MRI brain volume changes on a 54-month follow-up in 65 elderly controls with 3 neurocognitive assessments (baseline, 18 months, and 54 months), structural brain MRI (baseline and 54 months), brain amyloid PET during follow-up, and APOE genotyping. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised. Regression models were used to identify predictors of volume loss including time, age, sex, personality, amyloid load, presence of APOE ε4 allele, and cognitive evolution. Lower agreeableness factor scores (and 4 of its facets) were associated with lower volume loss in the hippocampus, entorhinal cortex, amygdala, mesial temporal lobe, and precuneus bilaterally. Higher openness factor scores (and 2 of its facets) were also associated with lower volume loss in the left hippocampus. Our findings persisted when adjusting for confounders in multivariable models. These data suggest that the combination of low agreeableness and high openness is an independent predictor of better preservation of brain volume in areas vulnerable to neurodegeneration.
MeSH Terms
- Aged
- Aged, 80 and over
- Amyloidogenic Proteins
- Apolipoproteins E
- Brain
- Cognition
- Cohort Studies
- Female
- Follow-Up Studies
- Humans
- Magnetic Resonance Imaging
- Male
- Neuroimaging
- Organ Size
- Personality
- Positron-Emission Tomography
Keywords
- Amyloid load
- Cognitive aging
- Cohort studies
- Personality
- Structural MRI
Previous studies have suggested that the association between APOE ɛ 4 and dementia is moderated by physical activity (PA), but the results remain inconclusive and longitudinal data on cognitive decline are missing. In this study, we examine whether there is a gene-environment interaction between APOE and PA on cognitive decline in older adults using 9-year follow-up data of three cohort studies. We followed 7,176 participants from three longitudinal cohort studies: Longitudinal Aging Study Amsterdam (LASA), InCHIANTI, and Rotterdam Study for 9 years. PA was assessed with self-reported questionnaires and was categorized in low, moderate, and high PA. Cognitive function was assessed with the Mini-Mental State Examination (MMSE) and cognitive decline was defined as a decrease of three points or more on the MMSE during 3 years follow-up. We fitted logistic regression models using generalized estimating equations adjusting for age, sex, education, depressive symptoms, and number of chronic disease. Interaction between APOE and PA was tested on multiplicative and additive scale. Cohorts were similar in most aspects but InCHIANTI participants were on average older and had lower education. APOE ɛ 4 carriers had higher odds of cognitive decline (odds ratio [OR] = 1.46, 95% confidence interval [CI]: 1.29-1.64) while PA was not significantly associated with cognitive decline overall (moderate PA: OR = 0.87, 0.67-1.13; high PA: OR = 0.71, 0.36-1.40). There was no evidence for an interaction effect between PA and APOE ɛ 4 in cognitive decline in older adults (APOE × moderate PA: p = .83; APOE × high PA: p = .90). Previous claims of a gene-environment interaction between APOE ɛ 4 and PA in cognitive decline are not supported by our results.
Keywords
- Gene–environment interaction
- InCHIANTI
- Longitudinal Aging Study Amsterdam
- Rotterdam Study
Some individuals who reach ages beyond 100 years in good cognitive health may be resilient against risk factors associated with cognitive decline. Exploring the processes underlying resilience may contribute to the development of therapeutic strategies that help to maintain cognitive health while aging. To identify individuals who escape cognitive decline until extreme ages and to investigate the prevalence of associated risk factors. The 100-plus Study is a prospective observational cohort study of community-based Dutch centenarians enrolled between 2013 and 2019 who were visited annually until death or until participation was no longer possible. The centenarians self-reported their cognitive health, as confirmed by a proxy. Of the 1023 centenarians approached for study inclusion, 340 fulfilled the study criteria and were included in analyses. Data analysis was performed from April 2019 to December 2019. Cognition was assessed using the Mini-Mental State Examination (MMSE). To identify centenarians who escape cognitive decline, this study investigated the association of baseline cognition with survivorship and cognitive trajectories for at least 2 years of follow-up using linear mixed models, adjusted for sex, age, and education. This study investigated the prevalence of apolipoprotein E (APOE) genotypes and cardiovascular disease as risk factors associated with cognitive decline. At baseline, the median age of 340 centenarians was 100.5 years (range, 100.0-108.2 years); 245 participants (72.1%) were female. The maximum survival estimate plateaued at 82% per year (95% CI, 77% to 87%) across centenarians who scored 26 to 30 points on the baseline MMSE (hazard ratio, 0.56; 95% CI, 0.42 to 0.75; P < .001), suggesting that an MMSE score of 26 or higher is representative of both cognitive and physical health. Among the 79 centenarians who were followed up for 2 years or longer, those with baseline MMSE score less than 26 experienced a decline in MMSE score of 1.68 points per year (95% CI, -2.45 to -0.92 points per year; P = .02), whereas centenarians with MMSE scores of 26 or higher at baseline experienced a decline of 0.71 point per year (95% CI, -1.08 to -0.35 points per year). For 73% of the centenarians with baseline MMSE scores of 26 or higher, no cognitive changes were observed, which often extended to ensuing years or until death. It is estimated that this group is representative of less than 10% of Dutch centenarians. In this group, 18.6% carried at least 1 APOE-ε4 allele, compared with 5.6% of the centenarians with lower and/or declining cognitive performance. Most centenarians who scored 26 or higher on the MMSE at baseline maintained high levels of cognitive performance for at least 2 years, in some cases despite the presence of risk factors associated with cognitive decline. Investigation of this group might reveal the processes underlying resilience against risk factors associated with cognitive decline.
MeSH Terms
- Aged, 80 and over
- Aging
- Apolipoprotein E4
- Cognition
- Female
- Humans
- Longitudinal Studies
- Male
- Mental Status and Dementia Tests
- Prospective Studies
The ε4 allele of the apolipoprotein E (APOE) gene, a risk factor for cognitive decline, is associated with alterations in medial temporal lobe (MTL) structure and function, yet little research has been dedicated to understanding how these alterations might interact to negatively impact cognition. To bridge this gap, the present study employed linear regression models to determine the extent to which APOE genotype (ε4 , ε4-) modifies interactive effects of baseline arterial spin labeling MRI-measured cerebral blood flow (CBF) and FreeSurfer-derived cortical thickness/volume (CT/Vo) in two MTL regions of interest (entorhinal cortex, hippocampus) on memory change in 98 older adults who were cognitively normal at baseline. Baseline entorhinal CBF was positively associated with memory change, but only among ε4 carriers with lower entorhinal CT. Similarly, baseline entorhinal CT was positively associated with memory change, but only among ε4 carriers with lower entorhinal CBF. Findings suggest that APOE ε4 carriers may experience concomitant alterations in neurovascular function and morphology in the MTL that interact to negatively affect cognition prior to the onset of overt clinical symptoms. Results also suggest the presence of distinct multimodal neural signatures in the entorhinal cortex that may signal relative risk for cognitive decline among this group, perhaps reflecting different stages of cerebrovascular compensation (early effective vs. later ineffective).
Keywords
- APOE ε4
- Aging
- Cerebral blood flow
- Cognitive decline
- Cortical thickness
Mesial temporal lobe (MTL) is prominently affected in normal aging and associated with neurodegeneration in AD. Whether or not MTL atrophy is dependent on increasing amyloid load before the emergence of cognitive deficits is still disputed. We performed a 4.5-year longitudinal study in 75 older community dwellers (48 women, mean age: 79.3 years) including magnetic resonance imaging at baseline and follow-up, positron emission tomography amyloid during follow-up, neuropsychological assessment at 18 and 55 months, and APOE genotyping. Linear regression models were used to identify predictors of the MTL volume loss. Amyloid load was negatively associated with bilateral MTL volume at baseline explaining almost 10.5% of its variability. In multivariate models including time of follow-up and demographic variables (older age, male gender), this percentage exceeded 35%. The APOE4 allele independently contributed another 6%. Cognitive changes had a modest but still significant negative association with MTL volume loss. Our data support a multifactorial model including amyloid deposition, older age, male gender, APOE4 allele, and slight decline of cognitive abilities as independent predictors of MTL volume loss in brain aging.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alleles
- Amyloidogenic Proteins
- Apolipoprotein E4
- Cognitive Reserve
- Female
- Follow-Up Studies
- Genotype
- Humans
- Longitudinal Studies
- Male
- Neuropsychological Tests
- Organ Size
- Positron-Emission Tomography
- Sex Factors
- Temporal Lobe
Keywords
- APOE
- Amyloid load
- Cognitive changes
- Mesial temporal lobe
- Normal aging
- Structural MRI
There is mounting evidence that long-term exposure to air pollution is related to accelerated cognitive decline in aging populations. Factors that influence individual susceptibility remain largely unknown, but may involve the apolipoprotein E genotype E4 (APOE-ε4) allele. We assessed whether the association between long-term exposure to ambient air pollution and cognitive decline differed by APOE-ε4 status and cognitive risk factors. The Washington Heights Inwood Community Aging Project (WHICAP) is a prospective study of aging and dementia. Neuropsychological testing and medical examinations occur every 18-24 months. We used mixed-effects models to evaluate whether the association between markers of ambient air pollution (nitrogen dioxide [NO ]), fine [PM ], and coarse [PM ] particulate matter) and the rate of decline in global and domain-specific cognition differed across strata defined by APOE-ε4 genotypes and cognitive risk factors, adjusting for sociodemographic factors and temporal trends. Among 4821 participants with an average of 6 years follow-up, higher concentrations of ambient air pollution were associated with more rapid cognitive decline. This association was more pronounced among APOE-ε4 carriers (p < 0.001). A one interquartile range increase in NO was associated with an additional decline of 0.09 standard deviations (SD) (95%CI -0.1, -0.06) in global cognition across biennial visits among APOE-ε4 positive individuals and a 0.07 SD (95%CI -0.09, -0.05) decline among APOE-ε4 negative individuals. Results for PM PM and cognitive domains were similar. The association between air pollutants and rate of cognitive decline also varied across strata of race-ethnicity with the association strongest among White non-Hispanic participants. These results add to the body of evidence on the adverse impact of ambient air pollution on cognitive aging and brain health and provide new insights into the genetic and behavioral factors that may impact individual susceptibility.
MeSH Terms
- Aged
- Air Pollutants
- Air Pollution
- Apolipoprotein E4
- Apolipoproteins E
- Cognitive Dysfunction
- Female
- Genotype
- Humans
- Male
- Prospective Studies
- Washington
Keywords
- APOE-ε4 allele
- Aging
- Air pollution
- Cognitive decline
- Cognitive risk factors
- Epidemiology
Late onset Alzheimer's disease (LOAD) is a progressive neurodegenerative disease with four well-established risk factors: age, APOE4 genotype, female chromosomal sex, and maternal history of AD. Each risk factor impacts multiple systems, making LOAD a complex systems biology challenge. To investigate interactions between LOAD risk factors, we performed multiple scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), and beta-amyloid assessment, in 16 months old male and female mice with humanized human APOE3 (hAPOE3) or APOE4 (hAPOE4) genes. Metabolomic analyses indicated a sex difference in plasma profile whereas APOE genotype determined brain metabolic profile. Consistent with the brain metabolome, gene and pathway-based RNA-Seq analyses of the hippocampus indicated increased expression of fatty acid/lipid metabolism related genes and pathways in both hAPOE4 males and females. Further, female transcription of fatty acid and amino acids pathways were significantly different from males. MRI based imaging analyses indicated that in multiple white matter tracts, hAPOE4 males and females exhibited lower fractional anisotropy than their hAPOE3 counterparts, suggesting a lower level of white matter integrity in hAPOE4 mice. Consistent with the brain metabolomic and transcriptomic profile of hAPOE4 carriers, beta-amyloid generation was detectable in 16-month-old male and female brains. These data provide therapeutic targets based on chromosomal sex and APOE genotype. Collectively, these data provide a framework for developing precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest.
MeSH Terms
- Age of Onset
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Animals
- Apolipoprotein E4
- Apolipoproteins E
- Brain
- Disease Models, Animal
- Female
- Genotype
- Humans
- Magnetic Resonance Imaging
- Male
- Metabolome
- Mice
- Mice, Transgenic
- Sex Characteristics
- Sex Chromosomes
Dementia severity can be empirically described by the latent dementia phenotype "δ" and its various composite "homologs". We have explored δ's blood-based protein biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) study. However, it would be convenient to replicate those associations in the Alzheimer's Disease Neuroimaging Initiative (ADNI). To this end, we recently engineered a δ homolog from observed cognitive performance measures common to both projects (i.e., "dT2A"). We used nine rationally chosen peripheral blood-based protein biomarkers as indicators of a latent variable "INFLAMMATION". We then associated that construct with dT2A in structural equation models adjusted for age, gender, depressive symptoms, and apolipoprotein E (APOE) ε4 allelic burden. Significant factor loadings and INFLAMMATION's association with dT2A were confirmed in random splits of TARCC's relatively large sample, and across biofluids in the ADNI. Nine proteins measured in serum (TARCC) or plasma (ADNI) explained ≅10% of dT2A's variance in both samples, independently of age, APOE, education, and gender. All loaded significantly on INFLAMMATION, and positively or negatively, depending on their known roles are PRO- or ANTI-inflammatory proteins, respectively. The parameters of interest were confirmed across random 50% splits of the TARCC's sample, and replicated across biofluids in the ADNI. These results suggest that SEM can be used to replicate biomarker findings across samples and biofluids, and that a substantial fraction of dementia's variance is attributable to peripheral blood-based protein levels.
Keywords
- ADNI
- Aging
- Cognition
- Dementia
- Intelligence
- TARCC
- g
Hippocampal volume loss (HVL), PET-documented brain amyloid accumulation, and APOE-ε4 status are predictive biomarkers of the transition from mild cognitive impairment to Alzheimer disease (AD). In asymptomatic cases, the role of these biomarkers remains ambiguous. In contrast to the idea that HVL occurs in late phases of neurodegeneration, recent contributions indicate that it might occur before abnormal amyloid PET occurrence in elderly subjects and that its severity could be only marginally related to APOE variants. Using a longitudinal design, we examined the determinants of HVL in our sample, i.e., brain amyloid burden and the presence of APOE-ε4, and made a longitudinal assessment of cognitive functions. We performed a 4.5-year longitudinal study on 81 elderly community dwellers (all right-handed;, 48 (59.3%) women; mean age 73.7 ± 3.7 years) including MRI at baseline and follow-up, PET amyloid during follow-up, neuropsychological assessment at 18 and 54 months, and APOE genotyping. All cases were assessed using a continuous cognitive score (CCS) that took into account the global evolution of neuropsychological performance. Linear regression models were used to identify predictors of HVL. There was a negative association between the CCS and HVL bilaterally. In multivariate models adjusting for demographic variables, the presence of APOE-ε4 was related to increased HVL bilaterally. A trend of significance was observed with respect to the impact of amyloid positivity on HVL in the left hemisphere. No significant interaction was found between amyloid positivity and the APOE-ε4 allele. The progressive decrement of neuropsychological performance is associated with HVL long before the emergence of clinically overt symptoms. In this cohort of healthy individuals, the presence of the APOE-ε4 allele was shown to be an independent predictor of worst hippocampal integrity in asymptomatic cases independently of amyloid positivity.
MeSH Terms
- Aged
- Aged, 80 and over
- Amyloid beta-Peptides
- Apolipoprotein E4
- Brain
- Cognitive Aging
- Female
- Hippocampus
- Humans
- Longitudinal Studies
- Magnetic Resonance Imaging
- Male
- Positron-Emission Tomography
Keywords
- APOE
- Aging
- Amyloid
- Hippocampus
Amyloid imaging, gray matter (GM) morphometry and diffusion tensor imaging (DTI) have all been used as predictive biomarkers in dementia. Our objective was to define the imaging profile of healthy elderly controls as a function of their cognitive trajectories and explore whether amyloid burden and white matter (WM) microstructure changes are associated with subtle decrement of neuropsychological performances in old age. We performed a 4.5-year longitudinal study in 133 elderly individuals who underwent cognitive testing at inclusion and follow-up, amyloid PET, MRI including DTI sequences at inclusion, and APOE epsilon 4 genotyping. All cases were assessed using a continuous cognitive score (CCS) taking into account the global evolution of neuropsychological performances. Data processing included region of interest analysis of amyloid PET analysis, GM densities and tract-based spatial statistics (TBSS)-DTI. Regression models were built to explore the association between the CCS and imaging parameters controlling for significant demographic and clinical covariates. Amyloid uptake was not related to the cognitive outcome. In contrast, GM densities in bilateral hippocampus were associated with worst CCS at follow-up. In addition, radial and axial diffusivities in left hippocampus were negatively associated with CCS. Amyloid load was associated with decreased VBM and increased radial and axial diffusivity in the same area. These associations persisted when adjusting for gender and APOE4 genotype. Importantly, they were absent in amygdala and neocortical areas studied. The progressive decrement of neuropsychological performances in normal aging is associated with volume loss and WM microstructure changes in hippocampus long before the emergence of clinically overt symptoms. Higher amyloid load in hippocampus is compatible with cognitive preservation in cases with better preservation of GM densities and WM microstructure in this area.
Keywords
- APOE genotyping
- amyloid deposition
- magnetic resonance imaging
- normal aging
- positron emission tomography
Literature suggests vascular endothelial growth factor A (VEGFA) is protective among those at highest risk for Alzheimer's disease (AD). Apolipoprotein E (APOE) ε4 allele carriers represent a highly susceptible population for cognitive decline, and VEGF may confer distinct protection among APOE-ε4 carriers. We evaluated interactions between cortical expression of 10 VEGF gene family members and APOE-ε4 genotype to clarify which VEGF genes modify the association between APOE-ε4 and cognitive decline. Data were obtained from the Religious Orders Study and Rush Memory and Aging Project (N = 531). Linear regression assessed interactions on global cognition. VEGF genes NRP1 and VEGFA interacted with APOE-ε4 on cognitive performance (p.fdr < 0.05). Higher NRP1 expression correlated with worse outcomes among ε4 carriers but better outcomes among ε4 noncarriers, suggesting NRP1 modifies the risk for poor cognitive scores based on APOE-ε4 status. NRP1 regulates angiogenesis, and literature suggests vessels in APOE-ε4 brains are more prone to leaking, perhaps placing young vessels at risk for ischemia. Results suggest that future therapeutics targeting brain angiogenesis should also consider ε4 allele status.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Apolipoprotein E4
- Cognitive Aging
- Cognitive Dysfunction
- Female
- Gene Expression
- Genetic Association Studies
- Genetic Predisposition to Disease
- Genotype
- Humans
- Male
- Neovascularization, Physiologic
- Neuropilin-1
- Vascular Endothelial Growth Factor A
Keywords
- APOE-ε4
- Aging
- Cognition
- Gene expression
- Vascular endothelial growth factor (VEGF)
The role of even the strongest genetic risk factor for Alzheimer's disease (AD), the apolipoprotein E (APOE) ε4 allele, in its etiology remains poorly understood. We examined molecular signatures of AD defined as differences in linkage disequilibrium patterns between AD-affected and -unaffected whites (2673/16,246), Hispanics (392/867), and African Americans (285/1789), separately. We focused on 29 polymorphisms from 5 genes in the APOE region emphasizing beneficial and adverse effects of the APOE ε2- and ε4-coding single-nucleotide polymorphisms, respectively, and the differences in the linkage disequilibrium structures involving these alleles between AD-affected and -unaffected subjects. Susceptibility to AD is likely the result of complex interactions of the ε2 and ε4 alleles with other polymorphisms in the APOE region, and these interactions differ across races/ethnicities corroborating differences in the adverse and beneficial effects of the ε4 and ε2 alleles. Our findings support complex race/ethnicity-specific haplotypes promoting and protecting against AD in this region. They contribute to better understanding of polygenic and resilient mechanisms, which can explain why even homozygous ε4 carriers may not develop AD.
MeSH Terms
- Alleles
- Alzheimer Disease
- Apolipoproteins E
- Continental Population Groups
- Haplotypes
- Heterozygote
- Homozygote
- Humans
- Linkage Disequilibrium
- Polymorphism, Single Nucleotide
- Risk Factors
Keywords
- APOE polymorphism
- Aging
- Alzheimer's disease
- Health span
- Life span
- Neurodegenerative disorders
Evidence suggests the ɛ4 allele of the apolipoprotein E (APOE) gene may accelerate an age-related process of cortical thickening and cerebral blood flow (CBF) reduction in the anterior cingulate cortex (ACC). Although the neural basis of this association remains unclear, evidence suggests it might reflect early neurodegenerative processes. However, to date, associations between cerebrospinal fluid (CSF) biomarkers of neurodegeneration, such as CSF tau, and APOE-related alterations in ACC cortical thickness (CTH) and CBF have yet to be explored. The current study explored the interaction of CSF tau and APOE genotype (ɛ4 , ɛ4-) on FreeSurfer-derived CTH and arterial spin labeling MRI-measured resting CBF in the ACC (caudal ACC [cACC] and rostral ACC [rACC]) among a sample of 45 cognitively normal older adults. Secondary analyses also examined associations between APOE, CTH/CBF, and cognitive performance. In the cACC, higher CSF tau was associated with higher CTH and lower CBF in ɛ4 , whereas these relationships were not evident in ɛ4-. In the rACC, higher CSF tau was associated with higher CTH for both ɛ4 and ɛ4-, and with lower CBF only in ɛ4 . Significant interactions of CSF tau and APOE on CTH/CBF were not observed in two posterior reference regions implicated in Alzheimer's disease. Secondary analyses revealed a negative relationship between cACC CTH and executive functioning in ɛ4 and a positive relationship in ɛ4-. Findings suggest the presence of an ɛ4-related pattern of increased CTH and reduced CBF in the ACC that is associated with biomarkers of neurodegeneration and subtle decrements in cognition.
Keywords
- APOE
- Aging
- Alzheimer’s disease
- cerebral blood flow
- cognition
- cognitive decline
- grey matter
- magnetic resonance imaging
- tau proteins
The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the [i]Lamp2[/i] gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch's membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD-namely, the accumulation of APOE, APOA1, clusterin, and vitronectin-adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch's membrane were reduced in [i]Lamp2[/i] knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.
MeSH Terms
- Aging
- Animals
- Basement Membrane
- Bruch Membrane
- Exocytosis
- Humans
- Lysosomal-Associated Membrane Protein 2
- Lysosomes
- Macular Degeneration
- Mice
- Mice, Knockout
- Phagocytosis
- Retina
- Retinal Pigment Epithelium
Keywords
- LAMP2
- aging
- lysosome
- retinal degeneration
APOE is a well-studied gene with multiple effects on aging and longevity. The gene has three alleles: e2, e3, and e4, whose frequencies vary by ethnicity. While the e2 is associated with healthy cognitive aging, the e4 allele is associated with Alzheimer's disease and early mortality and therefore its prevalence among people with extreme longevity (EL) is low. Using the PopCluster algorithm, we identified several ethnically different clusters in which the effect of the e2 and e4 alleles on EL changed substantially. For example, PopCluster discovered a large group of 1,309 subjects enriched of Southern Italian genetic ancestry with weaker protective effect of e2 (odds ratio [OR] = 1.27, p = .14) and weaker damaging effect of e4 (OR = 0.82, p = .31) on the phenotype of EL compared to other European ethnicities. Further analysis of this cluster suggests that the odds for EL in carriers of the e4 allele with Southern Italian genetic ancestry differ depending on whether they live in the United States (OR = 0.29, p = .009) or Italy (OR = 1.21, p = .38). PopCluster also found clusters enriched of subjects with Danish ancestry with varying effect of e2 on EL. The country of residence (Denmark or United States) appears to change the odds for EL in the e2 carriers.
MeSH Terms
- Aged, 80 and over
- Alleles
- Apolipoproteins E
- Ethnic Groups
- Europe
- European Continental Ancestry Group
- Female
- Humans
- Longevity
- Male
Keywords
- APOE
- Bioinformatics
- Human genetics
- Longevity
The CHARIOT PRO Main study is a prospective, non-interventional study evaluating cognitive trajectories in participants at the preclinical stage of Alzheimer's disease (AD) classified by risk levels for developing mild cognitive impairment due to AD (MCI-AD). The study aimed to characterize factors and markers influencing cognitive and functional progression among individuals at-risk for developing MCI-AD, and examine data for more precise predictors of cognitive change, particularly in relation to APOE ε4 subgroup. This single-site study was conducted at the Imperial College London (ICL) in the United Kingdom. Participants 60 to 85 years of age were classified as high, medium (amnestic or non-amnestic) or low risk for developing MCI-AD based on RBANS z-scores. A series of clinical outcome assessments (COAs) on factors influencing baseline cognitive changes were collected in each of the instrument categories of cognition, lifestyle exposure, mood, and sleep. Data collection was planned to occur every 6 months for 48 months, however the median follow-up time was 18.1 months due to early termination of study by the sponsor. 987 participants were screened, among them 690 participants were actively followed-up post baseline, of whom 165 (23.9%) were APOE ε4 carriers; with at least one copy of the allele. The mean age was 68.73 years, 94.6% were white, 57.4% were female, and 34.8% had a Family History of Dementia with a somewhat larger percentage in the APOE ε4 carrier group (42.4%) compared to the non-carrier group (32.4%). Over half of the participants were married and 53% had a Bachelor's or higher degree. Most frequently, safety events typical for this population consisted of upper respiratory tract infection (10.4%), falls (5.2%), hypertension (3.5%) and back pain (3.0%). Conclusion (clinical relevance): AD-related measures collected during the CHARIOT PRO Main study will allow identification and evaluation of AD risk factors and markers associated with cognitive performance from the pre-clinical stage. Evaluating the psycho-biological characteristics of these pre-symptomatic individuals in relation to their natural neurocognitive trajectories will enhance current understanding on determinants of the initial signs of cognitive changes linked to AD.
MeSH Terms
- Aged
- Aged, 80 and over
- Alzheimer Disease
- Anxiety
- Apolipoprotein E4
- Cognition
- Cognitive Dysfunction
- Cohort Studies
- Depression
- Efficiency
- Female
- Healthy Volunteers
- Humans
- Longitudinal Studies
- Male
- Mental Status and Dementia Tests
- Middle Aged
- Neuropsychological Tests
- Prospective Studies
- Risk Factors
- Sleep
- United Kingdom
- Work
Keywords
- Alzheimer Disease
- CHARIOT
- aging registry
- cognitive health
- pre-clinical
Alzheimer's disease (AD) has a higher prevalence among African Americans. Targeting cardiovascular and metabolic risk factors may be potential mechanisms to modify AD risk and address racial/ethnic disparities in AD dementia. This study investigated relationships among cardiovascular and metabolic risk factors, APOE genotype, AD biomarkers, and intracranial arterial blood flow in Whites and African Americans enriched for AD risk. 399 cognitively unimpaired adults from the Wisconsin Alzheimer's Disease Research Center completed physical and neuroimaging examinations. A 4D Flow MRI sequence (phase-contrast vastly under sampled isotropic projection imaging) measured intracranial arterial flow in the Circle of Willis. Linear mixed-effects regression models estimated relationships between risk factors and intracranial arterial flow and tested interactions with racial group, APOE genotype, and AD biomarkers, with separate models per risk factor. Higher fasting glucose was associated with lower intracranial arterial flow; no additional relationships between flow and risk factors were observed. Main effects of racial group were observed, without an interaction, indicating lower flow in African Americans compared to Whites. In race-stratified analyses, higher glucose and triglycerides were associated with lower flow for African Americans, but not for Whites. No main effects or interactions among risk factors, APOE, or AD biomarkers, and flow were observed. Elevated fasting glucose and triglycerides were associated with lower intracranial arterial flow; these relationships were more prominent in African Americans. Targeting metabolic risk factors may impact intracranial arterial health. Additional research is needed to determine if this will impact disparities in dementia prevalence.
MeSH Terms
- African Americans
- Aged
- Alzheimer Disease
- Biomarkers
- Blood Flow Velocity
- Cardiovascular Diseases
- Cerebrovascular Circulation
- European Continental Ancestry Group
- Female
- Humans
- Male
- Middle Aged
- Risk Factors
Keywords
- African Americans
- Alzheimer’s disease
- Apolipoprotein E4
- aging
- cerebrovascular circulation
- glucose
- metabolic syndrome
- neuroimaging
- risk factors
Use of anticholinergic medication is associated with an increased risk of cognitive impairment and/or dementia. Despite this, the impact of continuing medication with anticholinergic properties in those diagnosed with Alzheimer's Disease (AD) is not clear. Analysis of data from NILVAD, an 18-month randomized controlled trial of Nilvadipine in AD. Effects of ongoing Anticholinergic Cognitive Burden (ACB) on cognition (ADAS-Cog: Alzheimer's Disease Cog Subsection) and dementia severity (CDR-sb: Clinical Dementia Rating - Sum of Boxes/DAD: Disability Assessment for Dementia) over 18 months was evaluated adjusting for important clinical covariates. Just over one-quarter (27.90%, n = 142/510) of patients with mild to moderate AD were prescribed a potential/definite anticholinergic. While ACB score was not associated with greater progression on the ADAS-Cog/CDR-sb over time, a higher total ACB predicted greater dementia severity on the DAD, which persisted after robust covariate adjustment (β Coef: -1.53, 95% CI: -2.83 to -0.23, p = .021). There was a significant interaction between APOE ε4 status and ACB score, with carriers experiencing greater progression on both the CDR-Sb (β Coef: 0.36, 95% CI: 0.05-0.67, p = .021) and DAD (β Coef: -3.84, 95% CI: -7.65 to 0.03, p = .049). Ongoing use of anticholinergic medication was associated with greater dementia progression on the DAD, but not the CDR-sb. APOE ε 4 carriers may be particularly vulnerable to the effect of ongoing anticholinergic medication on dementia severity, with significant APOE ε 4 x ACB score interactions demonstrated on both the DAD and CDR-sb.
Keywords
- Alzheimers
- Cognitive aging
- Drug related
- Medication
Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative-funded project AETIONOMY. A total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published. Immunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center-specific factors. Immunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Alzheimer Disease
- Amyloid
- Biomarkers
- Cohort Studies
- Europe
- Female
- Humans
- Inflammation
- Male
- Middle Aged
- Parkinson Disease
- Sex Factors
- tau Proteins
Keywords
- Aging
- Alzheimer's disease
- Amyloid
- Biomarker
- Cerebrospinal fluid
- Inflammation
- Mild cognitive impairment
- Multicenter
- Parkinson's disease
- Tau
Non-focal prospective memory (PM) is sensitive to age-related decline; an additional impairment in focal PM is characteristic of mild stage Alzheimer's disease. This research explored whether, by mid-adulthood, the distinct demands of focal and non-focal PM expose differences in carriers of an [i]APOE[/i] ε4 allele, a genetic risk factor for Alzheimer's disease. Thirty-three young and 55 mid-age adults, differentiated by [i]APOE[/i] genotype, completed a category-decision task with a concurrent focal or non-focal PM demand. Only mid-age ε4 carriers showed a cost of carrying a focal PM intention. In addition, mid-age ε4 carriers showed a significantly greater cost of carrying a non-focal PM intention than young ε4 carriers, supporting a profile of accelerated aging. Consistency in the profile of cost differences observed in mid-age ε4 carriers and pathological aging may indicate premature vulnerability. Future research correlating a shift in PM performance with early genotype differences in brain-based markers of decline is important.
Keywords
- APOE
- Alzheimer’s disease
- aging
- mid-adulthood
- prospective memory
The APOEɛ4 allele is a well-known risk factor for Alzheimer's disease (AD). Previous research argues that higher education helps to preserve cognition in older adults with AD pathology because of its key role in cognitive reserve and resilience. To test if higher educational level buffers the effect of APOEɛ4 on cognition among older non-Hispanic Blacks. Participants were 849 non-demented older non-Hispanic Blacks (38.3% APOEɛ4 ), who underwent a comprehensive neuropsychological evaluation. Multiple linear regression models tested the relationship between APOEɛ4 status and twelve cognitive measures with education (up to high school and beyond high school) as a moderator. Education buffered the effects of the APOEɛ4 allele, such that there was no impact of APOEɛ4 status on word-list memory retention and working memory among participants with more than a high school degree. This pattern was not observed for ten other cognitive measures of verbal and visual episodic memory, semantic memory, executive function, and processing speed-although a similar trend was observed for switching ability in executive functioning. The buffering effect of education was stronger among women than men. Our findings suggest that genetic effects on late-life cognition may be modified by environmental factors such as educational attainment. These results are consistent with the framework of cognitive reserve such that engaging in cognitively enriching activities and acquiring skills and knowledge with more years of education may increase the capacity to maintain cognitive function despite high genetic risk for impairment.
MeSH Terms
- Adult
- African Americans
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Apolipoprotein E4
- Cognitive Reserve
- Educational Status
- Executive Function
- Female
- Humans
- Male
- Memory
- Memory, Episodic
- Memory, Short-Term
- Middle Aged
- Neuropsychological Tests
- Sex Characteristics
Keywords
- APOE
- African American
- Alzheimer’s disease
- cognitive reserve
- educational attainment
- episodic memory
- genetic risk
- neuropsychological evaluation
A number of efforts are underway to better understand the role of genetic variation in successful aging and longevity. However, to date, only two genes have been consistently associated with longevity in humans: APOE and FOXO3, with the APOE ɛ2 allele also protective against dementia. Recently, using an exome-wide SNP array approach, a missense variant CLEC3B c.316G>A (rs13963 p.S106G) was reported to associate with longevity in two independent cohorts of Japanese and Chinese participants. Interestingly, CLEC3B p.S106G is more frequent in Caucasian populations. Herein, we examined the frequency of CLEC3B p.S106G in a Caucasian series of 1,483 neurologically healthy individuals with a specific subset >80 years of age. Although our findings do not support an association between CLEC3B p.S106G and aging without neurological disease (p = .89), we confirmed the association between the APOE ε2 allele and better survival without neurological disease (p = .001). Further assessment of healthy aged cohorts that retain intact neurological function will be critical to understand the etiology of neurodegenerative disease and the role of age at risk.
Keywords
APOE
CLEC3B
- Aging
- Human genetics
- Human health
Questions remain about whether apolipoprotein E (APOE)-ε4 effects on cognitive decline are similar in men and women and how APOE-ε4 and age interact to influence decline in different cognitive domains. In sex-stratified analyses, baseline age-dependent associations between APOE-ε4 status and longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50-93, 6733 assessments). In men, older baseline age was associated with greater effects of APOE-ε4 on longitudinal decline in memory and executive function, detectible from baseline age of 64 and 68, respectively. In women, older baseline age was associated with greater APOE-ε4 effects on longitudinal decline in attention, detectible at baseline age of 66. No significant APOE-ε4 effects were found for language, visual-spatial ability, or processing speed. Results highlight the importance of considering sex and age when assessing APOE-ε4-associated vulnerability to cognitive decline.
MeSH Terms
- Age Factors
- Aged
- Alleles
- Apolipoprotein E4
- Cognition Disorders
- European Continental Ancestry Group
- Executive Function
- Female
- Humans
- Longitudinal Studies
- Male
- Memory
- Neuropsychological Tests
- Sex Factors
Keywords
- Aging
- Alzheimer's disease
- Apolipoprotein E ε4
- Cognitive decline
- Sex
The apolipoprotein E gene (APOE) ε4 allele has a strong and manifold impact on cognition and neuroimaging phenotypes in cognitively normal subjects, including alterations in the white matter (WM) microstructure. Such alterations have often been regarded as a reflection of potential thinning of the myelin sheath along axons, rather than pure axonal degeneration. Considering the main role of APOE in brain lipid transport, characterizing the impact of APOE on the myelin coating is therefore of crucial interest, especially in healthy APOE-ε4 homozygous individuals, who are exposed to a twelve-fold higher risk of developing Alzheimer's disease (AD), compared to the rest of the population. We examined T1w/T2w ratio maps in 515 cognitively healthy middle-aged participants from the ALFA study (ALzheimer and FAmilies) cohort, a single-site population-based study enriched for AD risk (68 APOE-ε4 homozygotes, 197 heterozygotes, and 250 non-carriers). Using tract-based spatial statistics, we assessed the impact of age and APOE genotype on this ratio taken as an indirect descriptor of myelin content. Healthy APOE-ε4 carriers display decreased T1w/T2w ratios in extensive regions in a dose-dependent manner. These differences were found to interact with age, suggesting faster changes in individuals with more ε4 alleles. These results obtained with T1w/T2w ratios, confirm the increased vulnerability of WM tracts in APOE-ε4 healthy carriers. Early alterations of myelin content could be the result of the impaired function of the ε4 isoform of the APOE protein in cholesterol transport. These findings help to clarify the possible interactions between the APOE-dependent non-pathological burden and age-related changes potentially at the source of the AD pathological cascade.
MeSH Terms
- Age Factors
- Aged
- Aging
- Apolipoprotein E4
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Myelin Sheath
- White Matter
Keywords
- Aging
- Alzheimer
- Apolipoprotein E
- Cognitively normal subjects
- Myelination
- T1w/T2w ratio
- White matter integrity
The ε4 allele of the apolipoprotein E (APOE) gene increases risk for cognitive decline in normal and pathologic aging. However, precisely how APOE ε4 exerts its negative impact on cognition is poorly understood. The present study aimed to determine whether APOE genotype (ε4 vs. ε4-) modifies the interaction of medial temporal lobe (MTL) resting cerebral blood flow (CBF) and brain structure (cortical thickness [CT], volume [Vo]) on verbal memory performance. Multiple linear regression models were employed to investigate relationships between APOE genotype, arterial spin labeling MRI-measured CBF and FreeSurfer-based CT and Vo in four MTL regions of interest (left and right entorhinal cortex and hippocampus), and verbal memory performance among a sample of 117 cognitively normal older adults (41 ε4 , 76 ε4-) between the ages of 64 and 89 (mean age = 73). Results indicated that APOE genotype modified the interaction of CBF and CT on memory in the left entorhinal cortex, such that the relationship between entorhinal CBF and memory was negative (lower CBF was associated with better memory) in non-carriers with higher entorhinal CT, positive (higher CBF was associated with better memory) in non-carriers with lower entorhinal CT, and negative (higher CBF was associated with worse memory) in ε4 carriers with lower entorhinal CT. Findings suggest that older adult APOE ε4 carriers may experience vascular dysregulation and concomitant morphological alterations in the MTL that interact to negatively affect memory even in the absence overt clinical symptoms, providing potential insight into the mechanistic link between APOE ε4 and detriments in cognition. Moreover, findings suggest a distinct multimodal neural signature in ε4 carriers (higher CBF and lower CT in the entorhinal cortex) that could aid in the identification of candidates for future clinical trials aimed at preventing or slowing cognitive decline. Differential findings with respect to ε4 carriers and non-carriers are discussed in the context of neurovascular compensation.
MeSH Terms
- Aged
- Aged, 80 and over
- Apolipoproteins E
- Cerebral Cortex
- Cerebrovascular Circulation
- Entorhinal Cortex
- Female
- Genotype
- Humans
- Linear Models
- Male
- Memory
- Middle Aged
Keywords
- APOE ε4
- Aging
- Alzheimer’s disease
- Cerebral blood flow
- Cognitive decline
- Cortical thickness
Episodic memory impairment is the hallmark symptom of Alzheimer's Disease (AD). However, episodic memory has also been shown to decline across the lifespan. Here, we investigated whether episodic memory is differentially affected relative to other cognitive abilities before old age, and whether being an Apolipoprotein E (APOE) ε4 carrier -a genetic risk factor for developing AD-exacerbates any such impairments. We used general linear models to test for performance differences within 4 composite measures of cognition - episodic memory, semantic memory, speed of processing, and fluid reasoning-- as a function of age group (young, Mage = 30.21 vs. middle-aged, Mage = 50.84) and APOE-ε4 genotype status (ε4 vs. ε4-). We replicated findings of age-related reductions in episodic memory, speed of processing, and fluid reasoning, and age-related increases in semantic memory. However, we also found that APOE genotype status moderated the age-related declines in episodic memory: APOE-ε4 middle-aged adults exhibited impairments relative to both APOE-ε4- middle-aged participants, and APOE-ε4 younger adults. These results suggest specific and dynamic alterations to episodic memory as a function of APOE allelic variation and age.
MeSH Terms
- Adult
- Alleles
- Alzheimer Disease
- Apolipoprotein E4
- Cognition
- Cognitive Aging
- Female
- Genotype
- Humans
- Linear Models
- Male
- Memory
- Memory, Episodic
- Middle Aged
- Young Adult
Keywords
- Alzheimer's diseas
- Apolipoprotein E
- Cognition
- Episodic memory
- Semantic memory
Cognitive-motor integration (CMI) involves concurrent thought and action which requires the interaction of large brain networks. Given that early-stage dementia involves neural network dysfunction, deficits in CMI may prove useful for early dementia detection. Our research objective was to investigate sex-related differences in the ability to integrate rules into action. Based on family medical history, we recruited male and female participants both with and without dementia risk factors. Participants did not demonstrate cognitive impairment at the time of testing. Participants were tested on four increasingly dissociated visuomotor tasks (eye and hand movements were made in different spatial planes and/or visual feedback was reversed). We observed significantly greater hand movement endpoint error scores and corrective path lengths in at-risk females compared to at-risk males in the most complex CMI condition (plane-change feedback reversal). Multiple regression analyses revealed both sex and family history as significant predictors of worse performance in a CMI condition requiring visual feedback reversal. Further, the regression analyses provided preliminary evidence that having an APOEɛ4 allele was a significant predictor of poorer CMI performance in the two plane-change CMI conditions. These data suggest that underlying brain networks controlling simultaneous thought and action may differ between the sexes in ways that may be clinically relevant in dementia progression. Preliminary data also suggest an important connection between APOE variant and CMI performance in individuals at risk of developing dementia.
MeSH Terms
- Aged
- Apolipoproteins E
- Cognition
- Cognitive Dysfunction
- Cross-Sectional Studies
- Dementia
- Female
- Humans
- Male
- Medical History Taking
- Middle Aged
- Photic Stimulation
- Psychomotor Performance
- Sex Characteristics
- Surveys and Questionnaires
Keywords
- Aging
- alzheimer’s disease
- apolipoprotein E4
- dementia risk
- geriatric
assessment
- motor skills
- movement
- visuomotor integration
The goal of this study was to compare regional brain atrophy patterns in cognitively unimpaired (CU) older adults with and without brain accumulation of amyloid-β (Aβ) to elucidate contributions of Aβ, age, and other variables to atrophy rates. In 80 CU participants from the Alzheimer's Disease Neuroimaging Initiative, we determined effects of Aβ and age on longitudinal, regional atrophy rates, while accounting for confounding variables including sex, APOE ε4 genotype, white matter lesions, and cerebrospinal fluid total and phosphorylated tau levels. We not only found overlapping patterns of atrophy in Aβ versus Aβ- participants but also identified regions where atrophy pattern differed between the 2 groups. Higher Aβ load was associated with increased longitudinal atrophy in the entorhinal cortex, amygdala, and hippocampus, even when accounting for age and other variables. Age was associated with atrophy in insula, fusiform gyrus, and isthmus cingulate, even when accounting for Aβ. We found age by Aβ interactions in the postcentral gyrus and lateral orbitofrontal cortex. These results elucidate the separate and related effects of age, Aβ, and other important variables on longitudinal brain atrophy rates in CU older adults.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Amyloid beta-Peptides
- Atrophy
- Brain
- Cognition
- Cognitive Dysfunction
- Databases, Factual
- Female
- Humans
- Longitudinal Studies
- Male
- Middle Aged
Keywords
- Aging
- Alzheimer's disease
- Amyloid-β
- Brain atrophy
To evaluate the risk of Alzheimer's disease-related neuropathology burden at autopsy given older adults' current cognitive state. Participants included 1,303 individuals who enrolled in the Religious Orders Study (ROS) and 1,789 who enrolled in the Rush Memory and Aging Project (MAP). Cognitive status was evaluated via standardized assessments of global cognition and episodic memory. At the time of analyses, about 50% of participants were deceased with the remaining numbers right censored. Using multi-state Cox proportional hazard models, we compared the cognitive status of all subjects alive at a given age and estimated future risk of dying with different AD-related neuropathologies. Endpoints considered were Braak Stages (0-2, 3-4, 5-6), CERAD (0, 1, 2, 3), and TDP-43 (0, 1, 2, 3) level. For all three pathological groupings (Braak, CERAD, TDP-43), we found that a cognitive test score one standard deviation below average put individuals at up to three times the risk for being diagnosed with late stage AD at autopsy according to pathological designations. The effect remained significant after adjusting for sex, APOE-e4 status, smoking status, education level, and vascular health scores. Applying multi-state modeling techniques, we were able to identify those at risk of exhibiting specific levels of neuropathology based on current cognitive test performance. This approach presents new and approachable possibilities in clinical settings for diagnosis and treatment development programs.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Cognitive Dysfunction
- Female
- Humans
- Male
- Middle Aged
Keywords
- Alzheimer’s disease
- Cognition
- Multi-state model
- Neuropathology
Age and apolipoprotein E (APOE) e4 genotype are two of the strongest known risk factors for sporadic Alzheimer's disease (AD). Neuroimaging has shown hemodynamic response changes with age, in asymptomatic carriers of the APOE e4 allele, and in AD. In this study, we aimed to characterize and differentiate age- and APOE gene-specific hemodynamic changes to breath-hold and visual stimulation. A further aim was to study whether these responses were modulated by 3-day intake of nitrate, a nitric oxide (NO) source. The study was designed as a randomized, double-blinded, placebo-controlled crossover study, and the study cohort comprised 41 APOE e4 carriers (e3/e4 or e4/e4 genotype) and 40 non-carriers (e3/e3 genotype) aged 30-70 years at enrollment. The participants underwent two scanning sessions, each preceded by ingestion of sodium nitrate or sodium chloride (control). During functional magnetic resonance imaging (fMRI) sessions, participants performed two concurrent tasks; a breath-hold task to probe cerebrovascular reactivity and a visual stimulation task to evoke functional hyperemia, respectively. We found that the blood oxygenation level dependent (BOLD) hemodynamic response to breath-hold was altered in APOE e4 carriers relative to non-carriers. Mid-aged (50-60 years of age) e4 carriers exhibited a significantly increased peak time relative to mid-aged e3 carriers, and peak time for younger (30-40 years of age) e4 carriers was significantly shorter than that of mid-aged e4 carriers. The response width was significantly increased for e4 carriers. The response peak magnitude significantly decreased with age. For the visual stimulation task, we found age-related changes, with reduced response magnitude with age but no significant effect of APOE allele type. We found no effect of nitrate ingestion on BOLD responses evoked by the breath-hold and visual stimulation tasks. The APOE gene-dependent response to breath-hold may reflect NO-independent differences in vascular function.
MeSH Terms
- Adult
- Aged
- Aging
- Apolipoprotein E3
- Apolipoprotein E4
- Apolipoproteins E
- Breath Holding
- Cerebrovascular Circulation
- Cross-Over Studies
- Double-Blind Method
- Female
- Genotype
- Hemodynamics
- Humans
- Longevity
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Nitrates
Keywords
- Ageing
- Alzheimer's disease
- Apolipoprotein E
- BOLD fMRI
- Breath-hold
- Cerebrovascular reactivity
The medial temporal lobe atrophy (MTA) and the posterior atrophy (PA) scales allow to assess the degree hippocampal and parietal atrophy from magnetic resonance imaging (MRI) scans. Despite reliable, easy and widespread employment, appropriate normative values are still missing. We aim to provide norms for the Italian population. Two independent raters assigned the highest MTA and PA score between hemispheres, based on 3D T1-weighted MRI of 936 Italian Brain Normative Archive subjects (age: mean ± SD: 50.2 ± 14.7, range: 20-84; MMSE>26 or CDR = 0). The inter-rater agreement was assessed with the absolute intraclass correlation coefficient (aICC). We assessed the association between MTA and PA scores and sociodemographic features and APOE status, and normative data were established by age decade based on percentile distributions. Raters agreed in 90% of cases for MTA (aICC = 0.86; 95% CI = 0.69-0.98) and in 86% for PA (aICC = 0.82; 95% CI = 0.58-0.98). For both rating scales, score distribution was skewed, with MTA = 0 in 38% of the population and PA = 0 in 52%, while a score ≥ 2 was only observed in 12% for MTA and in 10% for PA. Median denoted overall hippocampal (MTA: median = 1, IQR = 0-1) and parietal (PA: median = 0, IQR = 0-1) integrity. The 90th percentile of the age-specific distributions increased from 1 (at age 20-59) for both scales, to 2 for PA over age 60, and up to 4 for MTA over age 80. Gender, education and APOE status did not significantly affect the percentile distributions in the whole sample, nor in the subset over age 60. Our normative data for the MTA and PA scales are consistent with previous studies and overcome their main limitations (in particular uneven representation of ages and missing percentile distributions), defining the age-specific norms to be considered for proper brain atrophy assessment.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Atrophy
- Female
- Humans
- Italy
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Nervous System Diseases
- Reference Values
- Temporal Lobe
- Young Adult
Keywords
- Magnetic resonance imaging
- Medial temporal atrophy
- Normative values
- Posterior atrophy
- Visual assessment
Although the ε4 allele of the apolipoprotein E (APOE) gene and posttraumatic stress disorder (PTSD) have been linked to cognitive dysfunction and dementia risk, it is unknown whether they interact to predict cognitive dysfunction. We analyzed data from European-American (EA) veterans who participated in the National Health and Resilience in Veterans Study (NHRVS): main sample (n = 1,386) and primary replication sample (n = 509). EAs from the Yale-Penn Study cohort (n = 948) served as a second replication sample. Multivariable analyses were conducted to evaluate the predictive effects of ε4 carrier status and PTSD on cognitive functioning, with a focus on whether PTSD moderates the effect of ε4 carrier status. APOE ε4 allele carrier status (d = 0.15 and 0.17 in the main and primary replication NHRVS samples, respectively) and PTSD (d = 0.31 and 0.17, respectively) were independently associated with lower cognitive functioning. ε4 carriers with PTSD scored lower than those without PTSD (d = 0.68 and 1.29, respectively) with the most pronounced differences in executive function (d's = 0.75-1.50) and attention/concentration (d's = 0.62-1.33). A significant interaction was also observed in the Yale-Penn sample, with ε4 carriers with PTSD making more perseverative errors on a measure of executive function than those without PTSD (24.7% vs. 17.6%; d = 0.59). APOE ε4 allele carriers with PTSD have substantially greater cognitive difficulties than ε4 carriers without PTSD. These results underscore the importance of assessing, monitoring, and treating PTSD in trauma-affected individuals who are at genetic risk for cognitive decline and dementia.
MeSH Terms
- Alleles
- Apolipoprotein E4
- Cognition
- Cognitive Dysfunction
- Cohort Studies
- European Continental Ancestry Group
- Executive Function
- Female
- Genetic Predisposition to Disease
- Health Surveys
- Humans
- Male
- Middle Aged
- Polymorphism, Genetic
- Stress Disorders, Post-Traumatic
- United States
- Veterans
Keywords
- APOE
- PTSD
- aging
- cognitive decline
- genetics
- veterans
Longevity is mainly conditioned by genetic, epigenetic and environmental factors. Different genetic modifications seem to be positively associated to longevity, including SNPs in SIRT1, APOE, FOXO3A, ACE, ATM, NOS1 and NOS2 gene. Epigenetic changes as DNA hyper- and hypo-methylation influence significantly human longevity by activating/deactivating different genes involved in physiological mechanisms. Several studies have confirmed that centenarians have a lower DNA methylation content compared to young subjects, which showed more homogeneously methylated DNA region. Also the up-regulation of miR-21 seems to be more associated with longevity in different populations of long-lived subjects, suggesting its role as potential epigenetic biomarkers. A non-pharmacological treatment that seems to contrast age-related diseases and promote longevity is represented by dietary intervention. It has been evaluated the effects of dietary restriction of both single nutrients or total calories to extend lifespan. However, in daily practice it is very difficult to guarantee adherence/compliance of the subjects to dietary restriction and at the same time avoid dangerous nutritional deficiencies. As consequence, the attention has focused on a variety of substances both drugs and natural compounds able to mime the beneficial effects of caloric restriction, including resveratrol, quercetin, rapamycin, metformin and 2-deoxy-D-glucose.
MeSH Terms
- Diet Therapy
- Epigenomics
- Genetic Background
- Hormesis
- Humans
- Longevity
- Signal Transduction
Keywords
- Calorie restriction mimetic
- Dietary restriction
- Epigenetic mechanism
- Genetic modification
- Longevity
- Longevity molecular biomarkers
Stromal mesenchymal stem cells (MSCs) have the capability to self-renew and can differentiate into multiple cell types of the mesoderm germ layer, but their properties are affected by molecular aging mechanisms. MSCs can be obtained from adipose tissue termed as adipose-derived stem/stromal cells (ASCs) representing a promising tool for studying age-related diseases in detail. ASCs from young (16 weeks) and old (>108 weeks) rabbits were successfully isolated and propagated. ASCs showed the typical morphology and stained positive for CD105, Vimentin, Collagenase 1A, and negative for CD14, CD90, and CD73, demonstrating their mesenchymal origin. ASCs expressed MSC markers, including [i]MYC[/i], [i]KLF4[/i], [i]CHD1[/i], [i]REST[/i], and [i]KAT6A[/i], whereas pluripotency-related genes, such as [i]NANOG[/i], [i]OCT4[/i], and [i]SOX2[/i], were not expressed. Aged ASCs showed altered protein and mRNA levels of APOE, ATG7, FGF2, PTEN, and SIRT1. Adipogenic differentiation of old visceral ASCs was significantly decreased compared with young visceral ASCs. We successfully established rabbit ASC cultures representing an [i]in vitro[/i] model for the analysis of stem cell aging mechanisms. ASCs, obtained from old female rabbits, showed age- and source-specific alteration due to aging of the donor. Stem cell plasticity was altered with age as shown by reduced adipogenic differentiation capacity.
MeSH Terms
- Adipogenesis
- Adipose Tissue
- Aging
- Animals
- Biomarkers
- Cell Differentiation
- Cell Plasticity
- Cell Proliferation
- Cells, Cultured
- Female
- Mesenchymal Stem Cells
- Rabbits
Keywords
- adipogenic differentiation
- adipose-derived stem/stromal cells
- aging biomarkers
- and stem cell plasticity
- healthy aging
Recent findings outline negative effects of brain insulin signaling on memory due to hyperinsulinemia. We investigated the association between insulin resistance (IR) with AD and dementia. Later life Japanese men (N = 1544, mean age = 79.9 years) with normal cognitive function were followed from exam 4 to 5 of the Kuakini Honolulu Asia Aging Study. Subjects underwent physical exams, blood draws, and neuropsychological testing. IR status was determined at exam 4 using the McAuley and HOMA indices. Subjects with prevalent diabetes and dementia were excluded. Incident dementia and AD cases were determined at exam 5. IR was associated with decreased odds of AD and dementia using both IR indices. Carriers of the APOE ε4 allele had 15% increased odds of AD and dementia. Our findings provide insight regarding possible inverse relationship between IR and AD in elderly Japanese men, and support biologic studies showing short term hyperinsulinemia improves memory and cognitive function.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Follow-Up Studies
- Hawaii
- Humans
- Insulin Resistance
- Longitudinal Studies
- Male
Keywords
- Aging
- Alzheimer's disease
- Dementia
- Insulin resistance
Use latent class analysis (LCA) to identify patterns of cognitive functioning in a sample of older adults with clinical depression and without dementia and assess demographic, psychiatric, and neurobiological predictors of class membership. Neuropsychological assessment data from 121 participants in the Alzheimer's Disease Neuroimaging Initiative-Depression project (ADNI-D) were analyzed, including measures of executive functioning, verbal and visual memory, visuospatial and language functioning, and processing speed. These data were analyzed using LCA, with predictors of class membership such as depression severity, depression and treatment history, amyloid burden, and APOE e4 allele also assessed. A two-class model of cognitive functioning best fit the data, with the Lower Cognitive Class (46.1% of the sample) performing approximately one standard deviation below the Higher Cognitive Class (53.9%) on most tests. When predictors of class membership were assessed, carrying an APOE e4 allele was significantly associated with membership in the Lower Cognitive Class. Demographic characteristics, age of depression onset, depression severity, history of psychopharmacological treatment for depression, and amyloid positivity did not predict class membership. LCA allows for identification of subgroups of cognitive functioning in a mostly cognitively intact late life depression (LLD) population. One subgroup, the Lower Cognitive Class, more likely to carry an APOE e4 allele, may be at a greater risk for subsequent cognitive decline, even though current performance on neuropsychological testing is within normal limits. These findings have implications for early identification of those at greatest risk, risk factors, and avenues for preventive intervention.
MeSH Terms
- Age of Onset
- Aged
- Aged, 80 and over
- Aging
- Amyloid beta-Peptides
- Apolipoprotein E4
- Cognitive Dysfunction
- Depressive Disorder
- Female
- Humans
- Latent Class Analysis
- Male
- Models, Neurological
- Neuropsychological Tests
- Risk
- Severity of Illness Index
Keywords
- Aging
- Cognitive functioning
- Late life depression
- Latent class analysis
- Major depression
- Neuropsychology
Along with rapid global population aging, the age-related cognitive disorders such as mild cognitive impairment (MCI) and dementia have posed a serious threat to public health, health care system, and sustainable economic and societal development of all countries. In this narrative review, we seek to summarize the major epidemiological studies from the life-course perspective that investigate the influence of genetic susceptibility [e.g., apolipoprotein (APOE) ε4 allele] and intellectual or psychosocial factors (e.g., educational attainments and leisure activities) as well as their interactions on cognitive phenotypes in aging. Numerous population-based studies have suggested that early-life educational attainments and socioeconomic status, midlife work complexity and social engagements, late-life leisure activities (social, physical, and mentally-stimulating activities), certain personality traits (e.g., high neuroticism and low conscientiousness), and depression significantly affect late-life cognitive phenotypes. Furthermore, certain intellectual or psychosocial factors (e.g., leisure activities and depression) may interact with genetic susceptibility (e.g., APOE ε4 allele) to affect the phenotypes of cognitive aging such that risk or beneficial effects of these factors on cognitive function may vary by carrying the susceptibility genes. Current evidence from the randomized controlled trials that support the cognitive benefits of cognitive training among cognitive healthy older adults remains limited. The cognitive reserve hypothesis has been proposed to partly explain the beneficial effects of lifetime intellectual and psychosocial factors on late-life cognitive function. This implies that, from a life-course perspective, preventive intervention strategies targeting multiple modifiable intellectual and psychosocial factors could interfere with clinical expression of cognitive disorders in old age and delay the onset of dementia syndrome, and thus, may help achieve healthy brain aging.
Keywords
- cognitive aging
- cognitive reserve
- genetic susceptibility
- interaction
- life-course epidemiology
- psychosocial factors
The etiology of late-onset Alzheimer's disease is unknown. Recent epidemiological studies suggest that exposure to high levels of ozone (O ) may be a risk factor for late-onset Alzheimer's disease. Nonetheless, whether and how O exposure contributes to AD development remains to be determined. In this study, we tested the hypothesis that O exposure synergizes with the genetic risk factor APOE ε4 and aging leading to AD, using male apolipoprotein E (apoE)4 and apoE3 targeted replacement mice as men have increased risk exposure to high levels of O via working environments and few studies have addressed APOE ε4 effects on males. Surprisingly, our results show that O exposure impairs memory in old apoE3, but not old apoE4 or young apoE3 and apoE4, male mice. Further studies show that old apoE4 mice have increased hippocampal activities or expression of some enzymes involved in antioxidant defense, diminished protein oxidative modification, and neuroinflammation following O exposure compared with old apoE3 mice. These novel findings highlight the complexity of interactions between APOE genotype, age, and environmental exposure in AD development.
MeSH Terms
- Aging
- Alzheimer Disease
- Animals
- Apolipoprotein E3
- Apolipoprotein E4
- Environmental Exposure
- Genotype
- Male
- Memory Disorders
- Oxidative Stress
- Ozone
- Risk Factors
Keywords
- APOE genotype
- Aging
- Alzheimer's disease
- Oxidative stress
- Ozone
Microorganisms resident in our bodies participate in a variety of regulatory and pathogenic processes. Here, we describe how etiological pathways implicated in Alzheimer's disease (AD) may be regulated or disturbed by symbiotic microbial activity. Furthermore, the composition of symbiotic microbes has changed dramatically across human history alongside the rise of agriculturalism, industrialization, and globalization. We postulate that each of these lifestyle transitions engendered progressive depletion of microbial diversity and enhancement of virulence, thereby enhancing AD risk pathways. It is likely that the human life span extended into the eighth decade tens of thousands of years ago, yet little is known about premodern geriatric epidemiology. We propose that microbiota of the gut, oral cavity, nasal cavity, and brain may modulate AD pathogenesis, and that changes in the microbial composition of these body regions across history suggest escalation of AD risk. Dysbiosis may promote immunoregulatory dysfunction due to inadequate education of the immune system, chronic inflammation, and epithelial barrier permeability. Subsequently, proinflammatory agents-and occasionally microbes-may infiltrate the brain and promote AD pathogenic processes. APOE genotypes appear to moderate the effect of dysbiosis on AD risk. Elucidating the effect of symbiotic microbiota on AD pathogenesis could contribute to basic and translational research.
MeSH Terms
- Aging
- Alzheimer Disease
- Biological Evolution
- Brain
- Dysbiosis
- Gastrointestinal Microbiome
- Humans
- Inflammation
- Mouth
- Nasal Cavity
- Symbiosis
Keywords
- Alzheimer's disease
- dementia
- evolutionary medicine
- immunoregulation
- microbiome
Identified in 1993, APOE4 is the greatest genetic risk factor for Alzheimer's disease (AD), increasing risk up to 15-fold compared to the common variant APOE3. Since the mid 1990's, transgenic (Tg) mice have been developed to model AD pathology and progression, primarily via expression of the familial AD (FAD) mutations in the presence of mouse-APOE (m-APOE). APOE4, associated with enhanced amyloid-β (Aβ) accumulation, has rarely been the focus in designing FAD-Tg mouse models. Initially, FAD-Tg mice were crossed with human (h)-APOE driven by heterologous promoters to identify an APOE genotype-specific AD phenotype. These models were later supplemented with FAD-Tg mice crossed with APOE-knockouts (APOE or APOE-KO) and h-APOE-targeted replacement (h-APOE-TR) mice, originally generated to study the role of APOE genotype in peripheral lipid metabolism and atherosclerotic lesion development. Herein, we compare the m- and h-APOE multi-gene clusters, and then critically review the relevant history and approaches to developing a Tg mouse model to characterize APOE-dependent AD pathology, in combination with genetic (sex, age) and modifiable (e.g., inflammation, obesity) risk factors. Finally, we present recent data from the EFAD mice, which express 5xFAD mutations with the expression of the human apoE isoforms (E2FAD, E3FAD and E4FAD). This includes a study of 6- and 18-month-old male and female E3FAD and E4FAD, a comparison that enables examination of the interaction among the main AD risk factors: age, APOE genotype and sex. While no single transgenic mouse can capture the effects of all modifiable and genetic risk factors, going forward, a conscious effort needs to be made to include the factors that most significantly modulate AD pathology.
MeSH Terms
- Age Factors
- Alzheimer Disease
- Animals
- Apolipoproteins E
- Disease Models, Animal
- Female
- Male
- Mice, Transgenic
- Mutation
- Phenotype
- Sex Factors
- tau Proteins
Keywords
- APOE4 and AD risk
- Aging FAD-Tg mice
- Alzheimer's disease (AD)
- Apolipoprotein E
- EFAD-Tg mouse model
- Familial AD transgenic mice (FAD-Tg)
- sex and AD risk
Alzheimer's dementia is the leading cause of dementia in older adults and women are disproportionately burdened. It is increasingly recognized that dementia in older persons is related to the co-occurrence of mixed pathologies in the brain, but few studies have examined whether the frequency of common pathologies vary by sex. We examined the frequency of the most common mixed pathologies that underlie Alzheimer's dementia in aging, including Alzheimer's disease (AD) in combination with Lewy Bodies, cerebrovascular disease (CVD) pathology, or TDP-43/Hippocampal sclerosis, and determined whether the patterns differed for women and men in a combined cohort of over 1500 older community-dwelling adults. We found in separate models that women were significantly more likely to have AD and CVD pathology than men, and men were more likely to have "pure" Lewy Body disease, in models adjusted for age at death, education, race, and the APOE-e4 allele. Although AD with TDP-43/Hippocampal sclerosis pathology was greater in number in women than men, the difference was not significant after adjustments for age at death and other confounders. Together these findings suggest sex differences in mixed pathology, specifically AD with CVD in older adults from the community.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Brain
- Cerebrovascular Disorders
- Cohort Studies
- Dementia
- Female
- Humans
- Independent Living
- Lewy Bodies
- Lewy Body Disease
- Male
- Neuropathology
- Sex Characteristics
Keywords
- Alzhiemer's disease
- Community-dwelling
- Mixed pathology
- Sex differences
Sex differences in verbal episodic memory function have been widely reported. However, sex-specific effects on rates of episodic memory decline remain controversial, and evidence is particularly scarce in the oldest-old population. We aimed to investigate sex differences in trajectories of episodic memory performance in oldest-old individuals. Based on 13-year longitudinal data with 9 follow-up assessments of a large sample of cognitively unimpaired old (75 ) primary care patients (n = 3,254) participating in the German AgeCoDe/AgeQualiDe study, we used linear mixed effects analyses to model sex-specific trajectories of change in verbal episodic memory while accounting for covarying factors. We found that even in the highest age group women outperformed men in immediate (b = -1.71, p < 0.001) and delayed (b = -0.85, p < 0.001) free recall conditions. Associated late-life trajectories, however, did not differ significantly between the sexes. We further demonstrated that younger age, higher education, and an absence of depressive symptoms predicted better performance in both sexes. In contrast, past occurrences of stroke and APOE ɛ4 carrier status showed a negative relation to test scores. Our findings confirm previous research suggesting that women perform better in verbal episodic memory tests. We add that this advantage is still present in the oldest-old age groups. Our results indicate that sociodemographic and health related factors are as important as genetically based APOE ɛ4 carrier status in the prediction of normal cognitive development in advanced old age.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Apolipoprotein E4
- Cohort Studies
- Dementia
- Depression
- Disease Progression
- Educational Status
- Female
- Humans
- Linear Models
- Longitudinal Studies
- Male
- Memory Disorders
- Memory, Episodic
- Mental Recall
- Psychomotor Performance
- Sex Characteristics
- Socioeconomic Factors
- Verbal Learning
Keywords
- Cognition
- cohort study
- longitudinal
- oldest-old
- sex differences
- verbal episodic memory
There are conflicting results regarding how APOE genotype, the strongest genetic risk factor for Alzheimer's disease (AD), influences spatial and longitudinal amyloid-β (Aβ) deposition and its impact on the selection of biomarker cut-points. In our study, we sought to determine the impact of APOE genotype on cross-sectional and longitudinal florbetapir positron emission tomography (PET) amyloid measures and its impact in classification of patients and interpretation of clinical cohort results. We included 1,019 and 1,072 Alzheimer's Disease Neuroimaging Initiative participants with cerebrospinal fluid Aβ1 - 42 and florbetapir PET values, respectively. 623 of these subjects had a second florbetapir PET scans two years after the baseline visit. We evaluated the effect of APOE genotype on Aβ distribution pattern, pathological biomarker cut-points, cross-sectional clinical associations with Aβ load, and longitudinal Aβ deposition rate measured using florbetapir PET scans. 1) APOEɛ4 genotype influences brain amyloid deposition pattern; 2) APOEɛ4 genotype does not modify Aβ biomarker cut-points estimated using unsupervised mixture modeling methods if white matter and brainstem references are used (but not when cerebellum is used as a reference); 3) findings of large differences in Aβ biomarker value differences based on APOE genotype are due to increased probability of having AD neuropathology and are most significant in mild cognitive impairment subjects; and 4) APOE genotype and age (but not gender) were associated with increased Aβ deposition rate. APOEɛ4 carrier status affects rate and location of brain Aβ deposition but does not affect choice of biomarker cut-points if adequate references are selected for florbetapir PET processing.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Apolipoprotein E4
- Apolipoproteins E
- Biomarkers
- Cognitive Dysfunction
- Cross-Sectional Studies
- Female
- Genotype
- Humans
- Longitudinal Studies
- Male
- Middle Aged
- Positron-Emission Tomography
- Reference Values
- Sex Characteristics
- Tissue Distribution
Keywords
- Alzheimer’s disease
- amyloid-β
- cerebrospinal fluid
- diagnosis
- mild cognitive impairment
- positron emission tomography
The aim of this study was to determine the effects of apolipoprotein E ε4 (APOE ε4) genotype and sex together on longitudinal change in adjusted hippocampal volume [hippocampal volume:intracranial volume ratio (HpVR)] across the Alzheimer's disease (AD) continuum. At baseline, we included 372 individuals with normal cognition (NC), 738 individuals with mild cognitive impairment (MCI) and 271 patients with mild AD from the Alzheimer's Disease Neuroimaging Initiative database. We examined the effects of the APOE ε4 by sex interaction on longitudinal change in HpVR within the overall sample and within each diagnostic group. Female gender was found to be associated with longitudinal reduction of HpVR in the NC and MCI groups, but not in the AD group. Similarly, APOE ε4 was associated with longitudinal reduction of HpVR in the NC and MCI groups, but not in the AD group. Further, female APOE ε4 carriers showed a greater longitudinal reduction of HpVR than their male counterparts in the NC group, but not in the MCI or AD group. However, due to the relatively short duration of follow-up visits in patients with AD, further studies are needed to replicate these findings. Female APOE ε4 carriers show a greater longitudinal reduction of HpVR than their male counterparts in cognitively normal older adults.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Apolipoprotein E4
- Atrophy
- Cognition
- Cognitive Dysfunction
- Female
- Genotype
- Hippocampus
- Humans
- Longitudinal Studies
- Male
- Middle Aged
- Neuroimaging
- Reference Values
- Sex Characteristics
Keywords
apolipoprotein E ε4
magnetic resonance imaging
- Alzheimer's disease
- hippocampal atrophy
- sex difference
Aging is a major risk factor for both normal and pathological cognitive decline. However, individuals vary in their rate of age-related decline. We developed an easily interpretable composite measure of cognitive age, and related both the level of cognitive age and cognitive slope to sociodemographic, genetic, and disease indicators and examine its prediction of dementia transition. Using a sample of 19,594 participants from the Health and Retirement Study, cognitive age was derived from a set of performance tests administered at each wave. Our findings reveal different conclusions as they relate to levels versus slopes of cognitive age, with more pronounced differences by sex and race/ethnicity for absolute levels of cognitive decline rather than for rates of declines. We also find that both level and slope of cognitive age are inversely related to education, as well as increased for persons with APOE ε4 and/or diabetes. Finally, results show that the slope in cognitive age predicts subsequent dementia among non-demented older adults. Overall, our study suggests that this measure is applicable to cross-sectional and longitudinal studies on cognitive aging, decline, and dementia with the goal of better understanding individual differences in cognitive decline.
MeSH Terms
- Aged
- Cognition Disorders
- Cognitive Aging
- Cognitive Dysfunction
- Continental Population Groups
- Female
- Humans
- Male
- Metabolic Diseases
- Michigan
- Middle Aged
- Neuropsychological Tests
- Risk Factors
- Surveys and Questionnaires
Keywords
- APOE
- Aging
- Cognitive Decline
- Dementia
- Education
- Polygenic Risk Score
β-Amyloid deposits are a pathologic hallmark of Alzheimer disease (AD). However, the extent to which cortical β-amyloid protein in the absence of insoluble deposits is associated with classic features of AD appear to be unknown. To examine the associations of cortical β-amyloid protein in the absence of insoluble deposits with cognitive decline, neurofibrillary tangles, other age-associated neuropathologic conditions, and APOE. This analysis combines data from 2 community-based clinicopathologic cohort studies of aging. The Religious Orders Study started in 1994, and the Rush Memory and Aging Project started in 1997. Both studies are ongoing. Participants without known dementia were enrolled and agreed to annual clinical evaluations and brain donation after death. Primary analyses focused on individuals without β-amyloid deposits. Data analyses occurred in mid-September 2018. β-Amyloid protein abundance was measured by targeted proteomics using selected reaction monitoring. β-Amyloid deposits were detected using immunohistochemistry. Other neuropathologic indices were quantified via uniform structured evaluation. Linear mixed models were used to examine the association of β-amyloid protein with cognitive decline. Regression models examined the protein associations with neuropathologic outcomes and the APOE genotype. By mid-September 2018, 3575 older persons were enrolled, and 1559 had died and undergone brain autopsy. Proteomic data were collected in 1208 individuals, and 5 with missing cognitive scores were excluded. Of the remaining 1203, primary analyses focused on 148 individuals (12.3%) without β-amyloid deposits. In this group, the mean (SD) age at death was 87.0 (7.0) years, and 84 individuals (56.8%) were women. In the absence of β-amyloid deposits, we did not observe an association of β-amyloid protein with decline in episodic memory, but the protein was associated with faster rates of decline in processing speed (mean [SE] change, -0.014 [0.005]; P = .008) and visuospatial abilities (mean [SE] change, -0.013 [0.005]; P = .006). We did not observe protein association with paired helical filament tau tangle density. The protein was associated with amyloid angiopathy (odds ratio, 1.38 [95% CI, 1.15-1.67]; P < .001) but no other brain pathology. The associations with cognitive decline were unchanged after controlling for amyloid angiopathy. Neither APOE ε4 nor a polygenic Alzheimer risk score was associated with β-amyloid protein. Cortical β-amyloid protein was associated with faster cognitive decline in the absence of β-amyloid deposits, which supports the role of cortical soluble β-amyloid as a neurotoxic agent in aging. The lack of protein association with paired helical filament tau tangles, episodic memory decline, or strong genetic drivers of deposited β-amyloid suggests an underlying neuropathologic change that may differ from that of AD.
MeSH Terms
- Aged
- Aged, 80 and over
- Alzheimer Disease
- Amyloid beta-Peptides
- Apolipoprotein E4
- Autopsy
- Brain
- Cerebral Amyloid Angiopathy
- Cerebral Cortex
- Cognitive Aging
- Cognitive Dysfunction
- Cohort Studies
- Dementia
- Female
- Hippocampus
- Humans
- Immunohistochemistry
- Lewy Bodies
- Male
- Memory, Episodic
- Neurofibrillary Tangles
- Plaque, Amyloid
- Proteomics
- Sclerosis
- TDP-43 Proteinopathies
Amyloid positivity is a biomarker of AD pathology, yet the associations between amyloid positivity and brain volumetric changes, especially in the hippocampus, are inconsistent. We hypothesize that sex differences in associations may contribute to inconsistent findings among cognitively normal older adults. Using linear mixed effects models, we examined the association of amyloid positivity with prospective volumetric changes (mean = 3.3 visits) of parahippocampal gyrus (phg), hippocampus, entorhinal cortex (erc), precuneus, and fusiform gyrus among 171 Baltimore Longitudinal Study of Aging participants aged ≥55 years. Amyloid positivity was defined by a mean C-Pittsburgh Compound B (PiB) distribution volume ratio (DVR) cut-off of 1.062. All analyses included age, race, sex, education, APOE e4 carrier status, and two-way interactions of these covariates with time. Two-way interaction between sex and PiB /- status and three-way interaction of sex and PiB /- status with time were added to assess whether sex modified associations. PiB status was associated with greater volumetric declines in the phg (β = -0.036, SE = 0.011, p = 0.001) and erc (β = -0.019, SE = 0.009, p = 0.045). Sex modified the association of PiB status and rates of volumetric declines in fusiform (β = -0.117, SE = 0.049, p = 0.019). PiB males had steeper rates of volumetric declines in phg (β = -0.051, SE = 0.013, p < 0.001) and erc (β = -0.029, SE = 0.012, p = 0.014) than PiB- males, while there was no difference in rates of volumetric change between PiB and PiB- females. Amyloidosis is a marker of entorhinal and parahippocampal volume loss. Amyloid positivity is a predictor of volume loss in brain regions affected by early AD pathology in men, but not women.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Amyloid beta-Peptides
- Aniline Compounds
- Brain
- Female
- Humans
- Longitudinal Studies
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Positron-Emission Tomography
- Sex Characteristics
- Thiazoles
Keywords
- Amyloid
- Neurodegeneration
- PET
- Pittsburgh compound B
- Sex differences
Although previous studies have suggested that insulin plays a role in brain function, it still remains unclear whether or not insulin has a region-specific association with neuronal and synaptic activity in the living human brain. We investigated the regional pattern of association between basal blood insulin and resting-state cerebral glucose metabolism (CMglu), a proxy for neuronal and synaptic activity, in older adults. A total of 234 nondiabetic, cognitively normal (CN) older adults underwent comprehensive clinical assessment, resting-state 18F-fluodeoxyglucose (FDG)-positron emission tomography (PET) and blood sampling to determine overnight fasting blood insulin and glucose levels, as well as apolipoprotein E (APOE) genotyping. An exploratory voxel-wise analysis of FDG-PET without a priori hypothesis demonstrated a positive association between basal blood insulin levels and resting-state CMglu in specific cerebral cortices and hippocampus, rather than in non-specific overall cerebral regions, even after controlling for the effects of APOE e4 carrier status, vascular risk factor score, body mass index, fasting blood glucose, and demographic variables. Particularly, a positive association of basal blood insulin with CMglu in the right posterior hippocampus and adjacent parahippocampal region as well as in the right inferior parietal region remained significant after multiple comparison correction. Conversely, no region showed negative association between basal blood insulin and CMglu. Our finding suggests that basal fasting blood insulin may have association with neuronal and synaptic activity in specific cerebral regions, particularly in the hippocampal/parahippocampal and inferior parietal regions.
MeSH Terms
- Aged
- Aging
- Cerebral Cortex
- Female
- Fluorodeoxyglucose F18
- Glucose
- Hippocampus
- Humans
- Insulins
- Male
- Middle Aged
- Parahippocampal Gyrus
- Parietal Lobe
- Positron-Emission Tomography
Keywords
- Aging
- Cerebral glucose metabolism
- FDG-PET
- In vivo human brain imaging
- Insulin
- Region-specific association
- Voxel-wise analysis
Apolipoprotein (APOE) e4 genotype is an accepted risk factor for accelerated cognitive aging and dementia, though its neurostructural substrates are unclear. The deleterious effects of this genotype on brain structure may increase in magnitude into older age. This study aimed to investigate in UK Biobank the association between APOE e4 allele presence vs. absence and brain imaging variables that have been associated with worse cognitive abilities; and whether this association varies by cross-sectional age. We used brain magnetic resonance imaging (MRI) and genetic data from a general-population cohort: the UK Biobank (N = 8395 after exclusions). We adjusted for the covariates of age in years, sex, Townsend social deprivation scores, smoking history and cardiometabolic diseases. There was a statistically significant association between APOE e4 genotype and increased (i.e. worse) white matter (WM) hyperintensity volumes (standardised beta = 0.088, 95% confidence intervals = 0.036 to 0.139, P = 0.001), a marker of poorer cerebrovascular health. There were no associations with left or right hippocampal, total grey matter (GM) or WM volumes, or WM tract integrity indexed by fractional anisotropy (FA) and mean diffusivity (MD). There were no statistically significant interactions with age. Future research in UK Biobank utilising intermediate phenotypes and longitudinal imaging hold significant promise for this area, particularly pertaining to APOE e4's potential link with cerebrovascular contributions to cognitive aging.
Keywords
- APOE
- Aging
- Epidemiology
- Genetic association studies
- MRI
Neuropsychiatric symptoms (NPS) are a risk factor for cognitive impairment and are associated with cortical β-amyloid (Aβ) deposition. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging to examine the frequency of NPS among cognitively unimpaired (CU) and mild cognitive impairment (MCI) participants who either have normal (A-) or abnormal (A ) Aβ deposition. We also investigated whether combined presence of MCI and amyloid positivity (MCI/A ) is associated with greater odds of having NPS as compared to CU/A- (defined as reference group). Participants were 1627 CU and MCI individuals aged ≥ 50 years (54% males; median age 73 years). All participants underwent NPS assessment (Neuropsychiatric Inventory Questionnaire (NPI-Q); Beck Depression Inventory II (BDI-II); Beck Anxiety Inventory (BAI)) and C-PiB-PET. Participants with an SUVR > 1.42 were classified as A . We conducted multivariable logistic regression analyses adjusted for age, sex, education, and APOE ε4 genotype status. The sample included 997 CU/A-, 446 CU/A , 78 MCI/A-, and 106 MCI/A persons. For most NPS, the highest frequency of NPS was found in MCI/A and the lowest in CU/A-. The odds ratios of having NPS, depression (BDI ≥ 13), or anxiety (BAI ≥ 8, ≥ 10) were consistently highest for MCI/A participants. In conclusion, MCI with Aβ burden of the brain is associated with an increased risk of having NPS as compared to MCI without Aβ burden. This implies that the underlying Alzheimer's disease biology (i.e., cerebral Aβ amyloidosis) may drive both cognitive and psychiatric symptoms.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Anxiety
- Brain
- Cognitive Dysfunction
- Cross-Sectional Studies
- Depression
- Female
- Humans
- Logistic Models
- Male
- Middle Aged
- Neuropsychological Tests
- Positron-Emission Tomography
Apolipoprotein E (APOE) is a prominent genetic risk factor for Alzheimer's disease (AD) and a frequent target for associations with non-demented and cognitively impaired aging. APOE offers a unique opportunity to evaluate two dichotomous comparisons and selected gradations of APOE risk. Some evidence suggests that APOE effects may differ by sex and emerge especially in interaction with other AD-related biomarkers (e.g., vascular health). Longitudinal trajectories of non-demented adults (n = 632, 67% female, Mage = 68.9) populated a 40-year band of aging. Focusing on memory performance and individualized memory trajectories, a sequence of latent growth models was tested for predictions of (moderation between) APOE and pulse pressure (PP) as stratified by sex. The analyses (1) established robust benchmark PP effects on memory trajectories, (2) compared predictions of alternative dichotomous groupings (ε4- vs ε4 , ε2- vs ε2 ), and (3) examined precision-based predictions by disaggregated APOE genotypes. Healthier (lower) PP was associated with better memory performance and less decline. Therefore, all subsequent analyses were conducted in the interactive context of PP effects and sex stratification. The ε4-based dichotomization produced no differential genetic predictions. The ε2-based analyses showed sex differences, including selective protection for ε2-positive females. Exploratory follow-up disaggregated APOE genotype analyses suggested selective ε2 protection effects for both homozygotic and heterozygotic females. Precision analyses of AD genetic risk will advance the understanding of underlying mechanisms and improve personalized implementation of interventions.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Apolipoproteins E
- Blood Pressure
- Female
- Genetic Predisposition to Disease
- Genotype
- Humans
- Male
- Memory
- Middle Aged
- Sex Characteristics
Keywords
- Alzheimer's disease
- Apolipoprotein E
- Victoria
Longitudinal Study
- memory aging
- pulse pressure
- sex differences
- trajectory analyses.
The parallel decline of mobility and cognition with ageing is explained in part by shared brain structural changes that are related to fitness. However, the temporal sequence between fitness, brain structural changes and mobility loss has not been fully evaluated. Participants were from the Baltimore Longitudinal Study of Aging, aged 60 or older, initially free of cognitive and mobility impairments, with repeated measures of fitness (400-m time), mobility (6-m gait speed) and neuroimaging markers over 4 years (n = 332). Neuroimaging markers included volumes of total brain, ventricles, frontal, parietal, temporal and subcortical motor areas, and corpus callosum. Autoregressive models were used to examine the temporal sequence of each brain volume with mobility and fitness, adjusted for age, sex, race, body mass index, height, education, intracranial volume and APOE ɛ4 status. After adjustment, greater volumes of total brain and selected frontal, parietal and temporal areas, and corpus callosum were unidirectionally associated with future faster gait speed over and beyond cross-sectional and autoregressive associations. There were trends towards faster gait speed being associated with future greater hippocampus and precuneus. Higher fitness was unidirectionally associated with future greater parahippocampal gyrus and not with volumes in other areas. Smaller ventricle predicted future higher fitness. Specific regional brain volumes predict future mobility impairment. Impaired mobility is a risk factor for future atrophy of hippocampus and precuneus. Maintaining fitness preserves parahippocampal gyrus volume. Findings provide new insight into the complex and bidirectional relationship between the parallel decline of mobility and cognition often observed in older persons.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Atrophy
- Brain
- Female
- Humans
- Longitudinal Studies
- Male
- Physical Fitness
- Prospective Studies
- Walking Speed
Keywords
- brain atrophy
- fitness
- gait
- spatial distribution
- temporal sequence
Super-Seniors are healthy, long-lived individuals who were recruited at age 85 years or older with no history of cancer, cardiovascular disease, diabetes, dementia, or major pulmonary disease. In a 10-year follow-up, we aimed to determine whether surviving Super-Seniors showed compression of morbidity, and to test whether the allele frequencies of longevity-associated variants in APOE and FOXO3 were more extreme in such long-term survivors. Super-Seniors who survived and were contactable were re-interviewed 10 years after initial characterization. Health and lifestyle were characterized via questionnaire. Geriatric tests including the Timed Up and Go (TUG), Geriatric Depression Scale (GDS), Instrumental Activities of Daily Living (IADL) and the Mini-Mental State Exam (MMSE) were administered, and data were compared to results from on average 10 years earlier. As well, genotype and allele frequencies for SNPs rs7412 and rs429358 in APOE, and rs2802292 in FOXO3 were compared to the frequencies in the original collection of Super-Seniors and mid-life controls. Of the 480 Super-Seniors recruited from 2004 to 2007, 13 were alive, contactable, and consented to re-interview (mean age = 100.1 ± 3.3). Eight of these 13 participants (62%) still met Super-Senior health criteria. Diseases that occurred in late life were cardiovascular (5 of 13; 38%) and lung disease (1 of 13; 8%). MMSE and IADL scores declined in the decade between interviews, and GDS and TUG scores increased. The surviving group of centenarians had a higher frequency of APOE and FOXO3 longevity-associated variants even when compared to the original long-lived Super-Senior cohort. Although physical and mental decline occurred in the decade between interviews, the majority of Super-Seniors re-interviewed still met the original health criteria. These observations are consistent with reports of compression of morbidity at extreme ages, particularly in centenarians. The increased frequency of longevity- associated variants in this small group of survivors is consistent with studies that reported genetics as a larger contributor to longevity in older age groups.
MeSH Terms
- Activities of Daily Living
- Aged, 80 and over
- Aging
- Dementia
- Female
- Follow-Up Studies
- Genotype
- Humans
- Life Style
- Longevity
- Male
- Morbidity
- Polymorphism, Single Nucleotide
- Surveys and Questionnaires
- Time Factors
Keywords
- Centenarians
- Healthy aging
- Longevity
- Oldest-old
- Super-seniors
- To determine the longitudinal relationship between monocyte chemotactic protein 1 (MCP-1)/CCL2 and memory function in older adults. : We examined longitudinal plasma MCP-1/CCL2 levels and a longitudinal verbal memory measure (CVLT-II 20' recall) in a sample of 399 asymptomatic older adults (mean age = 72.1). Total visits ranged from 1 to 8, with an average time of 2.1 years between each visit, yielding 932 total observations. In order to isolate change over time, we decomposed MCP-1/CCL2 into subject-specific means and longitudinal deviations from the mean. The decomposed MCP-1/CCL2 variables were entered as predictors in linear mixed effects models, with age at baseline, sex, and education entered as covariates and recall as the longitudinal outcome. In follow-up analyses, we controlled for global cognition and [i]APOE[/i] genotype, as well as baseline vascular risk factors. We also examined the specificity of findings by examining the longitudinal association between the MCP-1/CCL2 variables and non-memory cognitive tests. : Within-subject increases in MCP-1/CCL2 levels were associated with decreases in delayed recall ([i]t[/i] = -2.65; [i]p[/i] = 0.01) over time. Results were independent of global cognitive function and APOE status ([i]t[/i] = -2.30, [i]p[/i] = 0.02), and effects remained when controlling for baseline vascular risk factors ([i]t[/i] = -1.92, [i]p[/i] = 0.05). No associations were noted between within-subject increases in MCP-1/CCL2 levels and other cognitive domains. : In an asymptomatic aging adult cohort, longitudinal increases in MCP-1/CCL2 levels were associated with longitudinal decline in memory. Results suggest that "healthy aging" is typified by early remodeling of the immune system, and that the chemokine, MCP-1/CCL2, may be associated with negative memory outcomes.
Keywords
- CCL2
- chemokines
- cognitive aging
- inflammation
- longitudinal
- memory
Innate immunity utilizes components of sensory signal transduction such as bitter and sweet taste receptors. In fact, empirical evidence has shown bitter and sweet taste receptors to be an integral component of antimicrobial immune response in upper respiratory tract infections. Since an efficient immune response plays a key role in the attainment of longevity, it is not surprising that the rs978739 polymorphism of the bitter taste receptor TAS2R16 gene has been shown to be associated with longevity in a population of 941 individuals ranging in age from 20 to 106 years from Calabria (Italy). There are many possible candidate genes for human longevity, however of the many genes tested, only APOE and FOXO3 survived to association in replication studies. So, it is necessary to validate in other studies genes proposed to be associated with longevity. Thus, we analysed the association of the quoted polymorphism in a population of long lived individuals (LLIs) and controls from another Italian population from Cilento. The analysis has been performed on data previously obtained with genome-wide association study on a population of LLIs (age range 90-109 years) and young controls (age range 18-45 years) from Cilento (Italy). Statistical power calculations showed that the analysed cohort represented by 410 LLIs and 553 young controls was sufficiently powered to replicate the association between rs978739 and the longevity phenotype according to the effect size and frequencies described in the previous paper, under a dominant and additive genetic model. However, no evidence of association between rs978739 and the longevity phenotype was observed according to the additive or dominant model. There are several reasons for the failure of the confirmation of a previous study. However, the differences between the two studies in terms of environment of the population adopted and of the criteria of inclusion have made difficult the replication of the findings.
Keywords
- Bitter taste receptors
- Case control study
- GWAS
- Innate immunity
- Longevity
- TAS2R16 gene
APOE4 is the greatest genetic risk factor for late-onset Alzheimer's disease (AD), increasing the risk of developing the disease by 3-fold in the 14% of the population that are carriers. Despite 25 years of research, the exact mechanisms underlying how APOE4 contributes to AD pathogenesis remain incompletely defined. APOE in the brain is primarily expressed by astrocytes and microglia, cell types that are now widely appreciated to play key roles in the pathogenesis of AD; thus, a picture is emerging wherein APOE4 disrupts normal glial cell biology, intersecting with changes that occur during normal aging to ultimately cause neurodegeneration and cognitive dysfunction. This review article will summarize how APOE4 alters specific pathways in astrocytes and microglia in the context of AD and the aging brain. APOE itself, as a secreted lipoprotein without enzymatic activity, may prove challenging to directly target therapeutically in the classical sense. Therefore, a deeper understanding of the underlying pathways responsible for APOE4 toxicity is needed so that more tractable pathways and drug targets can be identified to reduce APOE4-mediated disease risk.
Keywords
- APOE
- Alzheimer’s disease
- aging
- astrocytes
- microglia
Many individuals live to older ages without clinical impairment. It is unknown whether brain pathologies in these individuals are associated with subtle clinical deficits. We analyzed the brains of 161 clinically normal (Clinical Dementia Rating score = 0) older individuals enrolled in the Mayo Clinic Patient Registry or Study of Aging. We assessed for the presence and burden of beta-amyloid, tau, alpha-synuclein, TDP-43, and vascular pathology. We investigated whether pathologies were associated with antemortem cognitive and motor function, depression, MRI volumetric measures, or the apolipoprotein E (APOE) ε4 allele. Eighty-six percent had at least 1 pathology, and 63% had mixed pathologies. Tau and vascular pathology were associated with poorer memory scores. Tau was also associated with poorer general cognition scores and smaller amygdala, hippocampi, and entorhinal cortex volumes. Beta-amyloid neuritic plaque burden was associated with greater depression scores. The presence of a greater number of pathologies was associated with APOE e4 carrier status and with poorer memory performance. Some dementia-related pathologies are associated with poorer performance in clinical measures and brain atrophy in the unimpaired elderly.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Amyloid beta-Peptides
- Apolipoprotein E4
- Blood Vessels
- Brain
- Cognition
- DNA-Binding Proteins
- Depression
- Female
- Humans
- Male
- Memory
- Middle Aged
- Organ Size
- Psychomotor Performance
- alpha-Synuclein
- tau Proteins
Keywords
- Brain volume
- Clinically normal aging
- Cognition
- Depression
- Neurodegenerative pathology
- TDP-43
- Vascular pathology
Apolipoprotein E (APOE) effects on brain function remain controversial. Removal of APOE not only impairs cognitive functions but also reduces neuritic amyloid plaques in mouse models of Alzheimer's disease (AD). Can APOE simultaneously protect and impair neural circuits? Here, we dissociated the role of APOE in AD versus aging to determine its effects on neuronal function and synaptic integrity. Using two-photon calcium imaging in awake mice to record visually evoked responses, we found that genetic removal of APOE improved neuronal responses in adult APP/PSEN1 mice (8-10 mo). These animals also exhibited fewer neuritic plaques with less surrounding synapse loss, fewer neuritic dystrophies, and reactive glia. Surprisingly, the lack of APOE in aged mice (18-20 mo), even in the absence of amyloid, disrupted visually evoked responses. These results suggest a dissociation in APOE's role in AD versus aging: APOE may be neurotoxic during early stages of amyloid deposition, although being neuroprotective in latter stages of aging.
MeSH Terms
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Amyloid beta-Protein Precursor
- Amyloidosis
- Animals
- Apolipoproteins E
- Disease Models, Animal
- Evoked Potentials, Visual
- Humans
- Loss of Function Mutation
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Neuroglia
- Neurons
- Plaque, Amyloid
- Presenilin-1
- Regeneration
- Synapses
- Visual Cortex
The apolipoprotein E (APOE) gene is an established risk factor for sporadic Alzheimer's disease, with elevated risk for ε4-carriers and reduced risk for ε2-carriers. However, it is unclear whether APOE modifies risk for cognitive decline in normal aging. The objective of this study was to determine whether ε2 and ε4 are associated with rates of normal cognitive aging, and whether associations of ε4 with cognitive decline are modified by sex, education or health behaviors (exercise, alcohol consumption, smoking). A community-based sample of 1,393 older adults were genotyped for APOE and underwent cognitive assessment up to seven times over a maximum of period of 27 years. ε2-carriers showed slower executive function decline with age relative to ε3 homozygotes or ε4-carriers, whereas ε4-carriers demonstrated more rapid executive function and verbal fluency decline. Accelerated executive function decline was particularly pronounced in ε4-carriers with lower education. After excluding individuals with cognitive impairment, faster executive function decline was still apparent in ε4-carriers, and the effect of ε4 on episodic memory interacted with alcohol consumption, such that only ε4-carriers who did not drink showed more rapid memory decline than ε4 noncarriers. The influence of ε4 on cognitive aging did not differ by sex, nor was it modified by smoking or exercise. These findings indicate that the ε2 and ε4 alleles have differential effects on cognitive aging, and that negative effects of ε4 may be partly mitigated by behavioral choices. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Alleles
- Apolipoproteins E
- Cognitive Aging
- Cognitive Dysfunction
- Executive Function
- Female
- Genotype
- Heterozygote
- Humans
- Independent Living
- Male
- Middle Aged
- Neuropsychological Tests
While a number of single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) or cognitive impairment have been identified, independent replications remain the only way to validate proposed signals. We investigated SNPs in candidate genes associated with either cognitive impairment or AD pathogenesis and their relationships with probable dementia (PD) in the Women's Health Initiative Memory Study (WHIMS). We analyzed 96 SNPs across five genes (APOE/TOMM40, BDNF, COMT, SORL1, and KIBRA) in 2857 women (ages ≥65) from the WHIMS randomized trials of hormone therapy using a custom Illumina GoldenGate assay; 19% of the sample were MCI (N = 165) or PD (N = 387), and the remaining 81% were free of cognitive impairment. SNP associations were evaluated for PD in non-Hispanic whites adjusting for age and HT using logistic regression under an additive genetic model. One SNP (rs157582), located in the TOMM40 gene nearby APOE, was associated with the PD phenotype based on a P value accounting for multiple comparisons. An additional 12 SNPs were associated with the PD phenotype at P ≤ 0.05 (APOE: rs405509, rs439401; TOMM40: rs8106922, and KIBRA: rs4320284, rs11740112, rs10040267, rs13171394, rs6555802, rs2241368, rs244904, rs6555805, and rs10475878). Results of the sensitivity analyes excluding MCI were similar, with addition of COMT rs737865 and BDNF rs1491850 (P ≤ 0.05). Our results in older women provide supporting evidence that the APOE/TOMM40 genes confer dementia risk and extend these findings to COMT, BDNF, and KIBRA. Our findings may lead to a better understanding of the role these genes play in cognition and cognitive impairment.
MeSH Terms
- Aged
- Alzheimer Disease
- Apolipoproteins E
- Brain-Derived Neurotrophic Factor
- Catechol O-Methyltransferase
- Cognitive Dysfunction
- Dementia
- Female
- Genetic Predisposition to Disease
- Humans
- Intracellular Signaling Peptides and Proteins
- LDL-Receptor Related Proteins
- Membrane Transport Proteins
- Middle Aged
- Polymorphism, Single Nucleotide
- Postmenopause
- Women's Health
Keywords
- AD
- Alzheimer's disease
- MCI
- aging
- hormone therapy
Cerebral amyloid-β (Aβ) plaques are the hallmark biomarker of Alzheimer's disease (AD) and are detectable decades before clinical symptoms. Modifying risk factors associated with Aβ accrual offers an opportunity for AD prevention. While midlife vascular health is linked to AD; there is minimal longitudinal evidence regarding the effect of midlife lipids on Aβ. We examined the association between midlife lipids and Aβ 20 years later. One hundred and twenty-two women had serum lipid profiles in midlife (1992, 45-57 years), and cerebral imaging, genotyping, and cognition measured 20 years later (2012/13, 66-77 years). Imaging was performed in 2012/13 via F-18 Florbetaben positron emission tomography (PET) and standard uptake value ratios (SUVR) were calculated. Lipid profiles and other predictors of high PET-SUVR levels (>1.2) were evaluated using multivariable logistic regression. Increases in low-density lipoprotein (LDL) cholesterol in midlife were associated with Aβ, adjusting for age, education, cholesterol medication, and cognition (AdjOR1.81, 95% CI 1.08-3.01, p = 0.024), but attenuated on adjustment for apolipoprotein E4 (APOE ɛ4). Aβ risk increased in women with APOE ɛ4 and midlife cholesterol >6.2 mmol/L (AdjOR9.59, 95% CI 2.94-31.31, p < 0.001), APOE ɛ4 and LDL >3.3 mmol/L (AdjOR9.00, 95% CI 2.89-28.03, p < 0.001), and APOE ɛ4 and cholesterol to high-density lipoprotein ratio ≥3.25 (AdjOR8.32, 95% CI 2.32-29.89, p < 0.001). Presence of APOE ɛ4 and midlife dyslipidemia compounded the risk for Aβ deposition, although no independent effect of midlife lipids was found. Lipid-modifying treatment in midlife could mitigate the risk of Aβ in women with a genetic predisposition for AD. To better inform prevention, future consideration should be given toward managing dyslipidemia in women carrying the APOE ɛ4 allele.
MeSH Terms
- Aging
- Alleles
- Amyloid
- Apolipoprotein E4
- Brain
- Cohort Studies
- Dyslipidemias
- Female
- Humans
- Longitudinal Studies
- Middle Aged
- Plaque, Amyloid
Keywords
- Amyloid burden
- apolipoprotein
- cerebral amyloid
- dementia
- dyslipidemia
- positron emission tomography
- prevention
- serum lipid profile
- vascular health
The genetic background plays a role on longevity. The distribution of the apolipoprotein E gene (APOE) variants (ε2, ε3, ε4) may differ across age groups, especially in the oldest old and despite geographical and ethnic specificities. Since the ε4 variant is associated with Alzheimer's disease (AD), it might represent an opportunity for exploring the relationship of APOE with physiological and pathological aging. To explore the role played by APOE genotype/alleles on physiological and pathological brain aging. The study was conducted in a cohort of centenarians (n = 106), and two cohorts of octogenarians (without cognitive decline, n = 351 controls; and with AD, n = 294). No significant differences in genotype/allele distributions were observed comparing controls to centenarians. The prevalence of ε2/ε3, ε3/ε3, ε3/ε4 and ε4/ε4 genotypes were significantly different in centenarians compared to AD. The prevalence of ε2 and ε3 alleles were significantly higher in centenarians, whereas the ε4 was less frequent. The ε4 allele was positively associated with AD, whereas a negative association was found for ε2 and ε3 alleles. Our study indicates that ε4 allele is strongly associated with AD. APOE significantly affects AD risk, but apparently not longevity.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alleles
- Alzheimer Disease
- Apolipoprotein E2
- Apolipoprotein E3
- Apolipoprotein E4
- Cohort Studies
- Female
- Genotype
- Healthy Aging
- Humans
- Logistic Models
- Longevity
- Male
- Polymorphism, Genetic
- Registries
Keywords
- Alzheimer’s disease
- Apolipoprotein E
- Centenarians
- Longevity
White matter hyperintensities (WMH) of presumed vascular origin have been associated with an increased risk of Alzheimer's disease (AD). This study aims to describe the patterns of WMH associated with dementia risk estimates and individual risk factors in a cohort of middle-aged/late middle-aged individuals (mean 58 (interquartile range 51-64) years old). Magnetic resonance imaging and AD risk factors were collected from 575 cognitively unimpaired participants. WMH load was automatically calculated in each brain lobe and in four equidistant layers from the ventricular surface to the cortical interface. Global volumes and regional patterns of WMH load were analyzed as a function of the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) dementia risk score, as well as family history of AD and Apolipoprotein E (APOE) genotype. Additional analyses were performed after correcting for the effect of age and hypertension. The studied cohort showed very low WMH burden (median 1.94 cm ) and 20-year dementia risk estimates (median 1.47 %). Even so, higher CAIDE scores were significantly associated with increased global WMH load. The main drivers of this association were age and hypertension, with hypercholesterolemia and body mass index also displaying a minor, albeit significant, influence. Regionally, CAIDE scores were positively associated with WMH in anterior areas, mostly in the frontal lobe. Age and hypertension showed significant association with WMH in almost all regions analyzed. The APOE-ε2 allele showed a protective effect over global WMH with a pattern that comprised juxtacortical temporo-occipital and fronto-parietal deep white matter regions. Participants with maternal family history of AD had higher WMH load than those without, especially in temporal and occipital lobes. WMH load is associated with AD risk factors even in cognitively unimpaired subjects with very low WMH burden and dementia risk estimates. Our results suggest that tight control of modifiable risk factors in middle-age/late middle-age could have a significant impact on late-life dementia.
MeSH Terms
- Alzheimer Disease
- Brain
- Cognition
- Cohort Studies
- Female
- Humans
- Hypertension
- Male
- Middle Aged
- Risk Factors
- White Matter
Keywords
- Aging
- Brain
- Lesions
- Prevention
- Vascular
(1) To investigate atrophy patterns of hippocampal subfield volume and Alzheimer's disease (AD)-signature cortical thickness in mild cognitive impairment (MCI) patients; (2) to explore the association between the neuropsychological (NP) and the brain structure in the MCI and older normal cognition group; (3) to determine whether these associations were modified by the apolipoprotein E (APOE) ε4 gene and cognitive status. The FreeSurfer software was used for automated segmentation of hippocampal subfields and AD-signature cortical thickness for 22 MCI patients and 23 cognitive normal controls (NC). The volume, cortical thickness, and the neuropsychological scale were compared with two-sample t tests. Linear regression models were used to determine the association between the NP and the brain structure. Compared with the NC group, MCI patients showed a decreased volume of the left presubiculum, subiculum and right CA2_3 and CA4_DG (p < 0.05, FDR corrected). The volume of these regions was positively correlated with NP scores. Of note, these associations depended on the cognitive status but not on the APOE ε4 status. The left subiculum and presubiculum volume were positively correlated with the Montreal Cognitive Assessment (MoCA) scores only in the MCI patients. Atrophy of the hippocampal subfields may be a powerful biomarker for MCI in the Chinese population.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Apolipoprotein E4
- Biomarkers
- Cognition
- Cognitive Dysfunction
- Female
- Hippocampus
- Humans
- Magnetic Resonance Imaging
- Male
- Neuropsychological Tests
Keywords
- APOE ε4
- Cortical thickness
- Hippocampal subfield
- Mild cognitive impairment
To determine the rate of tau accumulation in healthy older adults (OA) and patients with Alzheimer disease (AD), as well as the relationship of tau accumulation to cortical atrophy. Two longitudinal flortaucipir (FTP) positron emission tomography (PET) and magnetic resonance imaging (MRI) scans were acquired from 42 OA (21 Pittsburg compound B [PiB] , age = 77.6 ± 4.6 years, 25 female [F]/17 male [M]) and 19 PiB patients with AD (age = 63.1 ± 10.3 years, 12 F/7 M) over 1 to 3 years of follow-up. FTP change, structural MRI measures of atrophy, and cross-modal correlations were examined on a voxelwise level. Regional annual percentage change in FTP was also calculated. Voxelwise FTP change in AD showed the greatest increases in lateral and medial frontal lobes. Atrophy over the same interval was more widespread and included posteromedial cortical areas, where tau accumulation rates were lower. In OA, FTP binding increased in bilateral temporal lobe and retrosplenial cortex, accompanied by atrophy in the same regions. There were no associations between voxelwise change in FTP and sex, PiB, or APOE. Regional FTP significantly increased at follow-up in OA and patients with AD. Mixed effects models showed greater FTP increases in AD compared to OA, and no differences within OA based on PiB status. Our findings indicate that tau accumulates even in amyloid-negative healthy OA and this process can be measured with in vivo tau-PET. In OA, tau accumulation and atrophy share a similar topography. In AD, tau increases more rapidly and accumulation occurs in frontal regions that are not yet undergoing significant atrophy. Ann Neurol 2019; 1-12 ANN NEUROL 2019;85:229-240.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Aniline Compounds
- Atrophy
- Brain
- Carbolines
- Case-Control Studies
- Cerebral Cortex
- Contrast Media
- Female
- Humans
- Longitudinal Studies
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Multimodal Imaging
- Organ Size
- Positron-Emission Tomography
- Thiazoles
- tau Proteins
To examine the effects of age and race on the association of apolipoprotein E (APOE) genotypes with cognitive decline in a population sample. Longitudinal study of 18 years' duration. Biracial urban US population sample. There were a total of 5807 participants, 60% African American (AA) and 40% European American (EA). A composite cognitive function based on individual tests of episodic memory, perceptual speed, and the Mini-Mental State Examination. The frequencies of APOE ε2/ε3 (14% vs 12%), ε2/ε4 (4% vs 2%), ε3/ε4 (29% vs 22%), and ε4/ε4 (4% vs 2%) genotypes were higher among AAs than EAs. After adjusting for demographic factors, the rate of decline in global cognition was twice as high among participants with the APOE ε4/ε4 genotype compared to participants with the APOE ε3/ε3 genotype (0.097 vs 0.048 SD units [SDUs] per year; P < .0001). This doubling was not different between AAs (0.091 vs 0.045 SDUs per year) and EAs (0.118 vs 0.059 SDUs per year) (P = .63). The APOE ε3/ε4 genotype was associated with a higher rate of decline with age (P = .021), while the APOE ε2/ε4 genotype (P = .016) and the APOE ε2/ε3 genotype (P = .043) were associated with a lower rate of decline with higher age. The APOE ε2/ε2 genotype was associated with a lower rate of decline in episodic memory, while the APOE ε2/ε4 was associated with a higher rate of decline in episodic memory and perceptual speed. The association of the APOE genotypes with cognitive decline was not different between AAs and EAs. However, individuals with different APOE genotypes showed a lower or a higher rate of decline with age. J Am Geriatr Soc 67:734-740, 2019.
MeSH Terms
- African Americans
- Aged
- Alleles
- Apolipoproteins E
- Cognitive Dysfunction
- European Continental Ancestry Group
- Female
- Genotype
- Humans
- Longitudinal Studies
- Male
- Neuropsychological Tests
- United States
Keywords
- APOE genotypes
- cognitive decline
- minority aging
Effects of Alzheimer's disease (AD) risk factors on brain volume changes may partly explain what happens during the preclinical AD stage in people who develop subsequent cognitive impairment (SI). We investigated predictors of neurodegeneration, measured by MRI-based volume loss, in older adults before diagnosis of cognitive impairment. There were 623 cognitively normal and 65 SI Baltimore Longitudinal Study of Aging participants (age 55-92 years) enrolled in the neuroimaging substudy from 1994 to 2015. Mixed-effects regression was used to assess the associations of AD risk factors (age, APOE e4 carrier status, diabetes, hypertension, obesity, current smoking, and elevated cholesterol) with brain regional volume change among the overall sample and by diagnostic status. Older age, APOE e4 carrier status, hypertension, and HDL cholesterol were predictors of volumetric change. Among SI participants only, hypertension, obesity, and APOE e4 carrier status were associated with greater declines in selected brain regions. SI individuals in the preclinical AD stage are vulnerable to risk factors that have either a protective or null effect in cognitively normal individuals.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Brain
- Cognition
- Cognitive Dysfunction
- Female
- Humans
- Male
- Middle Aged
- Neuroimaging
Keywords
- Cardiovascular risk factors
- Cognitive impairment
- Neurodegeneration
White matter microstructure can be measured with diffusion tensor imaging (DTI). While increasing age is a predictor of white matter (WM) microstructure changes, roles of other possible modifiers, such as cardiovascular risk factors, APOE ε4 allele status and biological sex have not been clarified. We investigated 665 cognitively normal participants from the Baltimore Longitudinal Study of Aging (age 50-95, 56.7% female) with a total of 1384 DTI scans. WM microstructure was assessed by fractional anisotropy (FA) and mean diffusivity (MD). A vascular burden score was defined as the sum of five risk factors (hypertension, obesity, elevated cholesterol, diabetes and smoking status). Linear mixed effects models assessed the association of baseline vascular burden on baseline and on rates of change of FA and MD over a mean follow-up of 3.6 years, while controlling for age, race, and scanner type. We also compared DTI trajectories in APOE ε4 carriers vs. non-carriers and men vs. women. At baseline, higher vascular burden was associated with lower FA and higher MD in many WM structures including association, commissural, and projection fibers. Higher baseline vascular burden was also associated with greater longitudinal decline in FA in the hippocampal part of the cingulum and the fornix (crus)/stria terminalis and splenium of the corpus callosum, and with greater increases in MD in the splenium of the corpus callosum. APOE ε4 carriers did not differ from non-carriers in baseline DTI metrics but had greater decline in FA in the genu and splenium of the corpus callosum. Men had higher FA and lower MD in multiple WM regions at baseline but showed greater increase in MD in the genu of the corpus callosum. Women showed greater decreases over time in FA in the gyrus part of the cingulum, compared to men. Our findings show that modifiable vascular risk factors (1) have a negative impact on white matter microstructure and (2) are associated with faster microstructural deterioration of temporal WM regions and the splenium of the corpus callosum in cognitively normal adults. Reducing vascular burden in aging could modify the rate of WM deterioration and could decrease age-related cognitive decline and impairment.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Apolipoprotein E4
- Corpus Callosum
- Diffusion Tensor Imaging
- Female
- Humans
- Longitudinal Studies
- Male
- Middle Aged
- Risk Factors
- Sex Factors
- Vascular Diseases
- White Matter
Keywords
- Aging
- Apolipoprotein ε4
- Diffusion tensor imaging (DTI)
- Vascular risk factors
- White matter microstructure
Despite evidence of a relationship between Apolipoprotein E (APOE) ε4 and later-life cognitive decline, the lifespan effects of carrying an ε4 allele on cognitive ageing are not well understood. Evidence of ε4 advantages in early-life are inconsistent, but not inconsiderable. We explored the proposal that APOE ε4 cognitive advantages arise only in response to complex and sensitive tasks targeting specific executive functions. We systematically manipulated executive demand within verbal fluency, decision-making, prospective memory, and sustained attention tasks. Participants aged 18-25 years (21 ε4 , 63 ε33) also completed a measure of subjective effort. Under low executive demand, ε4 made fewer verbal fluency word repeats compared to ε33 carriers. Under high executive demand, ε4 showed lower costs associated with performing concurrent tasks, greater switching errors, and more verbal fluency root repetition errors. Overall, ε4 appeared to be showing working memory updating advantages under conditions of low executive demand, more effective resource allocation under elevated levels of executive demand, and errors indicating different strategy use compared to ε33 carriers, including speed-accuracy trade-offs.
MeSH Terms
- Adolescent
- Adult
- Analysis of Variance
- Apolipoproteins E
- Attention
- Decision Making
- Executive Function
- Female
- Genotype
- Humans
- Male
- Memory, Episodic
- Neuropsychological Tests
- Photic Stimulation
- Reaction Time
- Verbal Behavior
- Young Adult
Keywords
- APOE ε4
- Cognitive aging
- Executive function
- Prospective memory
- Verbal fluency
- Young adults
In population studies, most individuals with mild cognitive impairment (MCI) do not progress to dementia in the near term, but rather remain stable MCI or revert to normal cognition. Here, we characterized MCI subgroups with different outcomes over 5 years. A population-based cohort (N=1603). Clinical Dementia Rating (CDR); self-reported medical conditions, subjective cognitive concerns, self-rated health, depressive symptoms, blood pressure, medications, blood pressure, APOE genotype, cognitive domain composite scores. We compared 3 MCI subgroups who progressed to dementia (n=86), stabilized at MCI (n=384), or reverted to normal (n=252), to those who remained consistently normal (n=881), defining MCI as CDR = 0.5 and dementia as CDR≥1. Using multinomial logistic regression models adjusted for demographics, we examined the associations of each group with selected baseline characteristics. With the normal group for reference, worse subjective cognitive concerns, functional impairments, self-rated health, and depressive symptoms were associated with being in any MCI group. Taking more prescription medications was associated with being in the stable MCI and reverter groups; diabetes and low diastolic blood pressure were associated with stable MCI. The APOE4 genotype was associated with stable and progressive MCI; stroke was associated with progressive MCI. All MCI subgroups were likely to have lower mean composite scores in all cognitive domains and more operationally defined impairments in attention, language, and executive function; reverters were more likely to lack memory and visuospatial impairments. MCI subgroups with different 5-year outcomes had some distinct characteristics suggesting different underlying causes. The progressors, unlike the reverters, had a profile broadly typical of Alzheimer's disease; the stable MCIs had other, including vascular, morbidity. These data shed light on the heterogeneity of MCI in the population. J Am Geriatr Soc 67:232-238, 2019.
MeSH Terms
- Aged
- Aged, 80 and over
- Apolipoprotein E4
- Blood Pressure
- Cognition
- Cognitive Dysfunction
- Cohort Studies
- Dementia
- Disease Progression
- Female
- Humans
- Logistic Models
- Male
- Stroke
Keywords
- aging
- cognition
- epidemiology
Primary age-related tauopathy (PART) is a recently described entity that can cause cognitive impairment in the absence of Alzheimer's disease (AD). Here, we compared neuropathological features, tau haplotypes, apolipoprotein E (APOE) genotypes, and cognitive profiles in age-matched subjects with PART and AD pathology. Brain autopsies (n = 183) were conducted on participants 85 years and older from the Baltimore Longitudinal Study of Aging and Johns Hopkins Alzheimer's Disease Research Center. Participants, normal at enrollment, were followed with periodic cognitive evaluations until death. Compared with AD, PART subjects showed significantly slower rates of decline on measures of memory, language, and visuospatial performance. They also showed lower APOE ε4 allele frequency (4.1% vs. 17.6%, P = .0046). Our observations suggest that PART is separate from AD and its distinction will be important for the clinical management of patients with cognitive impairment and for public health care planning.
MeSH Terms
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Apolipoprotein E4
- Autopsy
- Baltimore
- Brain
- Cognitive Dysfunction
- Genotype
- Humans
- Longitudinal Studies
- Memory
- Neuropathology
- Neuropsychological Tests
- Tauopathies
Keywords
- Aging
- Alzheimer disease (AD)
- Dementia
- Mild Cognitive Impairment (MCI)
- Neurofibrillary tangles
- Primary Age-Related Tauopathy (PART)
- Public Health Planning
The TOMM40-APOE variants are known for their strong, antagonistic associations with Alzheimer's disease and body weight. While a stronger role of the APOE than TOMM40 variants in Alzheimer's disease was suggested, comparative contribution of the TOMM40-APOE variants in the regulation of body weight remains elusive. We examined additive effects of rs2075650 and rs157580 TOMM40 variants and rs429358 and rs7412 APOE variants coding the ε2/ε3/ε4 polymorphism on body mass index (BMI) in age-aggregated and age-stratified cohort-specific and cohort-pooled analysis of 27,863 Caucasians aged 20-100 years from seven longitudinal studies. Minor alleles of rs2075650, rs429358, and rs7412 were individually associated with BMI (β = -1.29, p = 3.97 × 10 ; β = -1.38, p = 2.78 × 10 ; and β = 0.58, p = 3.04 × 10 , respectively). Conditional analysis with rs2075650 and rs429358 identified independent BMI-lowering associations for minor alleles (β = -0.63, p = 3.99 × 10 and β = -0.94, p = 2.17 × 10 , respectively). Polygenic mega-analysis identified additive effects of the rs2075650 and rs429358 heterozygotes (β = -1.68, p = 3.00 × 10 ), and the strongest BMI-lowering association for the rs2075650 heterozygous and rs429358 minor allele homozygous carriers (β = -4.11, p = 2.78 × 10 ). Conditional analysis with four polymorphisms identified independent BMI-lowering (rs2075650, rs157580, and rs429358) and BMI-increasing (rs7412) associations of heterozygous genotypes with BMI. Age-stratified conditional analysis revealed well-powered support for a differential and independent association of the rs429358 heterozygote with BMI in younger and older individuals, β = 0.58, 95% confidence interval (CI) = -1.18, 2.35, p = 5.18 × 10 for 3,068 individuals aged ≤30 years and β = -4.28, CI = -5.65, -2.92, p = 7.71 × 10 for 6,052 individuals aged >80 years. TOMM40 and APOE variants are independently and additively associated with BMI. The APOE ε4-coding rs429358 polymorphism is associated with BMI in older individuals but not in younger individuals.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Apolipoproteins E
- Body Mass Index
- Cohort Studies
- Genetic Association Studies
- Genotype
- Humans
- Linkage Disequilibrium
- Membrane Transport Proteins
- Middle Aged
- Multivariate Analysis
- Polymorphism, Single Nucleotide
Keywords
TOMM40
- ApoE polymorphism
- age-dependent effect
- aging
- body mass index
- health span
- lifespan
To investigate the effect of Apolipoprotein E (APOE) genotype on the association between dietary polyunsaturated fat (PUFA), cognitive function, and cerebral glutamate. A participant sample of 122 middle-aged adults were grouped according to APOE genotype (ϵ4 carrier or ϵ4 non-carrier) and asked to record dietary intake for three consecutive days. All participants also underwent neuropsychological testing and a proton magnetic resonance spectroscopy ( H MRS) scan to assess glutamate in the posterior cingulate cortex. Results: Multiple regression analyses revealed a significant interaction between APOE genotype and PUFA intake on memory performance, [i]F[/i](1,113) = 6.749, [i]p [/i]= .016. Greater PUFA intake was associated with better memory performance in healthy middle-aged adults who were APOE ϵ4 non-carriers, but not for ϵ4 carriers. Furthermore, there was a significant interaction between APOE genotype and PUFA intake on cerebral glutamate, in that dietary PUFA was associated with greater cerebral glutamate in APOE ϵ4 carriers, but not for ϵ4 non-carriers, [i]F[/i](1,114) = 5.173, [i]p[/i] = .025. The findings suggest that PUFA action on the brain differs according to APOE polymorphism and points towards cerebral glutamate as a potential marker of genetic risk for Alzheimer's disease (AD). Early treatment consisting of PUFA supplementation that is tailored to APOE genotype may be an important intervention for the prevention of cognitive decline.
Keywords
- Aging
- Alzheimer's disease
- Apolipoprotein E
- Diet
- Memory
- Polyunsaturated fat
- Proton magnetic resonance spectroscopy
Background and Purpose- Little is known about associations between vascular growth factors and magnetic resonance imaging (MRI) markers in midlife. We investigated the association of serum VEGF (vascular endothelial growth factor), Ang2 (angiopoietin 2), sTie2 (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2), and HGF (hepatocyte growth factor) concentrations with MRI markers of brain aging in middle-aged adults. Methods- We evaluated 1853 participants (mean age, 46±9 years; 46% men) from the Framingham Heart Study. Serum growth factor concentrations were measured using standardized immunoassays. Outcomes included total brain, cortical and subcortical gray matter, white matter, cerebrospinal fluid, and white matter hyperintensity volumes derived from MRI; as well as fractional anisotropy in white matter tracts from diffusion tensor imaging. We related VEGF, Ang2, sTie2, and HGF to MRI measures using multivariable regression models adjusting for vascular risk factors. We tested for interactions with APOE (apolipoprotein E) genotype and CRP (C-reactive protein). Results were corrected for multiple comparisons. Results- Higher sTie2 was associated with smaller total brain (estimate by SD unit±SE=-0.08±0.02, P=0.002) and larger white matter hyperintensity (0.08±0.02, P=0.002) volumes. Furthermore, higher Ang2 (0.06±0.02, P=0.049) and HGF (0.09±0.02, P=0.001) were associated with larger cerebrospinal fluid volumes. Finally, higher Ang2 was associated with decreased fractional anisotropy, in APOE-ε4 carriers only. Conclusions- Vascular growth factors are associated with early MRI markers of small vessel disease and neurodegeneration in middle-aged adults.
MeSH Terms
- Adult
- Aging
- Anisotropy
- Apolipoproteins E
- Atrophy
- Brain
- C-Reactive Protein
- Cerebral Small Vessel Diseases
- Diffusion Tensor Imaging
- Female
- Gray Matter
- Hepatocyte Growth Factor
- Humans
- Longitudinal Studies
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Organ Size
- Receptor, TIE-2
- Vascular Endothelial Growth Factor A
- Vesicular Transport Proteins
- White Matter
Keywords
- C-reactive protein
- aging
- angiogenic proteins
- apolipoprotein E4
- magnetic resonance imaging
Although the incidence of dementia increases exponentially with age, some individuals reach more than 100 years with fully retained cognitive abilities. To identify the characteristics associated with the escape or delay of cognitive decline, we initiated the 100-plus Study ( www.100plus.nl ). The 100-plus Study is an on-going prospective cohort study of Dutch centenarians who self-reported to be cognitively healthy, their first-degree family members and their respective partners. We collect demographics, life history, medical history, genealogy, neuropsychological data and blood samples. Centenarians are followed annually until death. PET-MRI scans and feces donation are optional. Almost 30% of the centenarians agreed to post-mortem brain donation. To date (September 2018), 332 centenarians were included in the study. We analyzed demographic statistics of the first 300 centenarians (25% males) included in the cohort. Centenarians came from higher socio-economic classes and had higher levels of education compared to their birth cohort; alcohol consumption of centenarians was similar, and most males smoked during their lifetime. At baseline, the centenarians had a median MMSE score of 25 points (IQR 22.0-27.5); most centenarians lived independently, retained hearing and vision abilities and were independently mobile. Mortality was associated with cognitive functioning: centenarians with a baseline MMSE score ≥ 26 points had a mortality percentage of 17% per annual year in the second year after baseline, while centenarians with a baseline MMSE score < 26 points had a mortality of 42% per annual year (p = 0.003). The cohort was 2.1-fold enriched with the neuroprotective APOE-ε2 allele relative to 60-80 year-old population controls (p = 4.8 × 10 ), APOE-ε3 was unchanged and the APOE-ε4 allele was 2.3-fold depleted (p = 6.3 × 10 ). Comprehensive characterization of the 100-plus cohort of cognitively healthy centenarians might reveal protective factors that explain the physiology of long-term preserved cognitive health.
MeSH Terms
- Aged, 80 and over
- Apolipoproteins E
- Cognition
- Dementia
- Educational Status
- Female
- Health Status
- Humans
- Life Style
- Male
- Netherlands
- Neuropsychological Tests
- Prospective Studies
- Socioeconomic Factors
- Surveys and Questionnaires
Keywords
- 100-plus Study
- Centenarians
- Cognitive health longevity
- Prospective cohort study
To date, candidate gene and genome-wide association studies (GWAS) have led to the discovery of longevity-associated variants (LAVs) in genes such as FOXO3A and APOE. Unfortunately, translating variants into drug targets is challenging for any trait, and longevity is no exception. Interdisciplinary and integrative multi-omics approaches are needed to understand how LAVs affect longevity-related phenotypes at the molecular physiologic level in order to leverage their discovery to identify new drug targets. The NIA convened a workshop in August 2017 on emerging and novel in silico (i.e., bioinformatics and computational) approaches to the translation of LAVs into drug targets. The goal of the workshop was to identify ways of enabling, enhancing, and facilitating interactions among researchers from different disciplines whose research considers either the identification of LAVs or the mechanistic or causal pathway(s) and protective factors they influence for discovering drug targets. Discussions among the workshop participants resulted in the identification of critical needs for enabling the translation of LAVs into drug targets in several areas. These included (1) the initiation and better use of cohorts with multi-omics profiling on the participants; (2) the generation of longitudinal information on multiple individuals; (3) the collection of data from non-human species (both long and short-lived) for comparative biology studies; (4) the refinement of computational tools for integrative analyses; (5) the development of novel computational and statistical inference techniques for assessing the potential of a drug target; (6) the identification of available drugs that could modulate a target in a way that could potentially provide protection against age-related diseases and/or enhance longevity; and (7) the development or enhancement of databases and repositories of relevant information, such as the Longevity Genomics website ( https://www.longevitygenomics.org ), to enhance and help motivate future interdisciplinary studies. Integrative approaches that examine the influence of LAVs on molecular physiologic phenotypes that might be amenable to pharmacological modulation are necessary for translating LAVs into drugs to enhance health and life span.
MeSH Terms
- Drug Delivery Systems
- Humans
- Longevity
- National Institute on Aging (U.S.)
- United States
Keywords
- Health and life span
- Integrative omics
- Protective factors
- Systems biology
- Target identification
Subtle alterations in dendritic spine morphology can induce marked effects on connectivity patterns of neuronal circuits and subsequent cognitive behavior. Past studies of rodent and nonhuman primate aging revealed reductions in spine density with concomitant alterations in spine morphology among pyramidal neurons in the prefrontal cortex. In this report, we visualized and digitally reconstructed the three-dimensional morphology of dendritic spines from the dorsolateral prefrontal cortex in cognitively normal individuals aged 40-94 years. Linear models defined relationships between spines and age, Mini-Mental State Examination, apolipoprotein E (APOE) ε4 allele status, and Alzheimer's disease (AD) pathology. Similar to findings in other mammals, spine density correlated negatively with human aging. Reduced spine head diameter associated with higher Mini-Mental State Examination scores. Individuals harboring an APOE ε4 allele displayed greater numbers of dendritic filopodia and structural alterations in thin spines. The presence of AD pathology correlated with increased spine length, reduced thin spine head diameter, and increased filopodia density. Our study reveals how spine morphology in the prefrontal cortex changes in human aging and highlights key structural alterations in selective spine populations that may promote cognitively normal function despite harboring the APOE ε4 allele or AD pathology.
MeSH Terms
- Adult
- Aged
- Aging
- Alzheimer Disease
- Apolipoprotein E4
- Cognition
- Cognitive Aging
- Dendritic Spines
- Female
- Genetic Predisposition to Disease
- Humans
- Male
- Middle Aged
- Neuronal Plasticity
- Prefrontal Cortex
Keywords
- APOE
- Aging
- Alzheimer's disease
- Dementia
- Dendritic spine
- Prefrontal cortex
- Resiliency
Candidate gene studies and genome-wide association studies found that genetic variation in APOE is robustly associated with multiple age-related diseases and longevity. Apolipoprotein E (ApoE) is an apolipoprotein that plays an important role in triglyceride and cholesterol metabolism. In literature, especially the ApoE ɛ4 isoform has been associated with an increased risk of mortality and age-related diseases such as Alzheimer's disease (AD), cardiovascular diseases (CVD), as compared to the "neutral" ApoE ɛ3 isoform. There are, however, large differences in the deleterious effects of the ApoE ɛ4 isoform between ancestries and populations, which might be explained by differences in environmental and lifestyle exposures. In this respect, poor nutrition and physical inactivity are two important lifestyle factors that have been associated with increased risks for AD and CVD. Therefore, in this narrative review, we discuss how omega-3 fatty acid intake and physical activity may modify the impact of ApoE ɛ4 on AD and CVD risk.
MeSH Terms
- Aging
- Alzheimer Disease
- Apolipoprotein E4
- Cardiovascular Diseases
- Environmental Exposure
- Genome-Wide Association Study
- Humans
- Risk Factors
The special design of the Long Life Family Study provides a unique opportunity to investigate the genetics of human longevity by analyzing data on exceptional lifespans in families. In this article, we performed two series of genome wide association studies of human longevity which differed with respect to whether missing lifespan data were predicted or not predicted. We showed that the use of predicted lifespan is most beneficial when the follow-up period is relatively short. In addition to detection of strong associations of SNPs in APOE, TOMM40, NECTIN2, and APOC1 genes with longevity, we also detected a strong new association with longevity of rs1927465, located between the CYP26A1 and MYOF genes on chromosome 10. The association was confirmed using data from the Health and Retirement Study. We discuss the biological relevance of the detected SNPs to human longevity.
MeSH Terms
- Aged
- Aged, 80 and over
- Apolipoprotein C-I
- Apolipoproteins E
- Calcium-Binding Proteins
- Chromosomes, Human, Pair 10
- Chromosomes, Human, Pair 19
- Denmark
- Female
- Gene Frequency
- Genome-Wide Association Study
- Humans
- Logistic Models
- Longevity
- Longitudinal Studies
- Male
- Membrane Proteins
- Membrane Transport Proteins
- Muscle Proteins
- Nectins
- Pedigree
- Polymorphism, Single Nucleotide
- Retinoic Acid 4-Hydroxylase
- United States
Amygdala is a group of nuclei involved in the neural circuits of fear, reward learning, and stress. The main goal of this magnetic resonance imaging (MRI) study was to investigate the relationship between age and the amygdala subnuclei volumes in a large cohort of healthy individuals. Our second goal was to determine effects of the apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF) polymorphisms on the amygdala structure. One hundred and twenty-six healthy participants (18-85 years old) were recruited for this study. MRI datasets were acquired on a 4.7 T system. Amygdala was manually segmented into five major subdivisions (lateral, basal, accessory basal nuclei, and cortical, and centromedial groups). The BDNF (methionine and homozygous valine) and APOE genotypes (ε2, homozygous ε3, and ε4) were obtained using single nucleotide polymorphisms. We found significant nonlinear negative associations between age and the total amygdala and its lateral, basal, and accessory basal nuclei volumes, while the cortical amygdala showed a trend. These age-related associations were found only in males but not in females. Centromedial amygdala did not show any relationship with age. We did not observe any statistically significant effects of APOE and BDNF polymorphisms on the amygdala subnuclei volumes. In contrast to APOE ε2 allele carriers, both older APOE ε4 and ε3 allele carriers had smaller lateral, basal, accessory basal nuclei volumes compared to their younger counterparts. This study indicates that amygdala subnuclei might be nonuniformly affected by aging and that age-related association might be gender specific.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Amygdala
- Apolipoproteins E
- Brain-Derived Neurotrophic Factor
- Cognitive Aging
- Female
- Healthy Aging
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Sex Factors
- Young Adult
Keywords
- aging
- amygdala subnuclei
- apolipoprotein E (APOE)
- brain-derived neurotrophic factor (BDNF)
- magnetic resonance imaging
We tested if the ε4 major isoform of the APOE gene and rs405509 and rs440446 promoter and intron-1 polymorphisms predicted risk of any dementia or Alzheimer's disease with diagnoses derived from the Hospital Discharge and Causes of Death Registers in 1453 participants of the Helsinki Birth Cohort Study. We used Cox proportional hazard models adjusted for sex, year of birth, maximum lifetime occupational status and education, and diagnoses of stroke, coronary heart disease, mood disorders, and depressive symptoms. APOE ε4 predicted higher risk of any dementia (hazard ratios >3.68; 95% confidence interval [CI] 1.76, 7.70) across all statistical models, and when adjusted for rs405509 and rs440446. The number of minor alleles in rs405509 or rs440446 was not associated with dementia risk (hazard ratios<1.43; 95% CI 0.87, 2.36). As rs405509 or rs440446 has been associated with nonpathological cognitive aging in this and other cohorts independent of the APOE major isoforms, these findings lend credence that APOE locus may be linked with dementia risk and nonpathological cognitive aging via separate mechanisms.
MeSH Terms
- Aged
- Alzheimer Disease
- Apolipoprotein E4
- Cognitive Aging
- Cohort Studies
- Dementia
- Female
- Finland
- Forecasting
- Humans
- Introns
- Male
- Polymorphism, Genetic
- Promoter Regions, Genetic
- Protein Isoforms
- Risk
Keywords
- APOE
- Alzheimer's disease
- Cohort studies
- Dementia
Chronic inflammation has been linked with geriatric-related conditions, including dementia. Inflammatory cytokine levels, including interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF) α, in the blood have been associated with cognitive impairment and decline. However, evidence has been mixed. We examined the cross-sectional and longitudinal associations between baseline-measured IL-6, IL-10, and TNFα levels and the ratio of IL-6/IL-10 with cognitive test performance and mild cognitive impairment (MCI) among 1,602 community-dwelling older adults (median age = 72.8) enrolled in the Mayo Clinic Study of Aging. Approximately half (46.5%) of participants were female and 98.6% were white. At baseline and follow-up visits (occurring at 15-month intervals), participants completed neuropsychological testing, blood draws, and had a clinical consensus diagnosis. In multivariable cross-sectional analyses, we did not observe an association between inflammatory cytokine levels and global or domain-specific cognitive z scores; however, higher IL-6 and IL-10 levels were associated with greater odds of a MCI diagnosis. Longitudinally, we did not observe any association between inflammatory cytokine levels and cognitive test performance or risk of MCI. Sex, age, cognitive status, APOE ε4 genotype, diabetes, depression, and cerebral amyloid-beta deposition were not effect modifiers. These results suggest that plasma inflammatory markers may not be useful to ascertain risk for cognitive decline and MCI in the general population.
MeSH Terms
- Aged
- Aging
- Biomarkers
- Cognitive Dysfunction
- Cross-Sectional Studies
- Female
- Humans
- Interleukin-10
- Interleukin-6
- Longitudinal Studies
- Male
- Tumor Necrosis Factor-alpha
Keywords
- Epidemiology
- Inflammation
- Mild cognitive impairment
Cerebral White Matter Hyperintensity (WMH) lesions have been identified as markers of cerebrovascular diseases and they are associated with increased risk of cognitive impairment. In this study, we investigated the relationship between midlife cardiovascular risk factors and late life WMH volumes two decades later, and examined their association with cognitive performance. 135 participants from the Women's Healthy Ageing Project had completed midlife cardiovascular risk measurement in 1992 and late life brain MRI scan and cognitive assessment in 2012. In these community-dwelling normal aging women, we found that higher midlife Framingham Cardiovascular Risk Profile (FCRP) score was associated with greater WMH volume two decades later, and was predominantly driven by the impact of HDL cholesterol level, controlling for age, education and APOE ε4 status. Structural equation modelling demonstrated that the relationship between midlife FCRP score and late life executive function was mediated by WMH volume. These findings suggest intervention strategies that target major cardiovascular risk factors at midlife might be effective in reducing the development of WMH lesions and thus late life cognitive decline.
MeSH Terms
- Aged
- Aging
- Brain
- Cardiovascular Diseases
- Cholesterol, HDL
- Cognition
- Cognition Disorders
- Cognitive Dysfunction
- Female
- Humans
- Leukoaraiosis
- Longitudinal Studies
- Magnetic Resonance Imaging
- Middle Aged
- Neuropsychological Tests
- Risk Factors
- White Matter
Keywords
- Cognitive domains
- Elderly women
- Framingham cardiovascular risk profile score
- Midlife cardiovascular risk factors
- White matter hyperintensity volume
Women reportedly make up two-thirds of Alzheimer's disease (AD) dementia sufferers. Many estimates regarding AD, however, are based on clinical series lacking autopsy confirmation. The Florida Autopsied Multi-Ethnic (FLAME) cohort was queried for AD cases with a total of 1625 identified ranging in age from 53 to 102 years at death. Standard neuropathologic procedures were employed and clinical information was retrospectively collected. Clinicopathologic and genetic data (MAPT and APOE) were stratified by sex. Within the neuropathologically diagnosed AD cohort, the overall number of women and men did not differ. Men were younger at onset of cognitive symptoms, had a shorter disease duration, and more often had atypical (non-amnestic) clinical presentations. The frequency of autopsy-confirmed AD among women and men stratified by age at death revealed an inverse U-shaped curve in men and a U-shaped curve in women, with both curves having inflections at approximately 70 years of age. Regional counts of neurofibrillary tangles differed in women and men, especially when examined by age intervals. Women had overall greater severity of neurofibrillary tangle counts compared to men, especially in the hippocampus. Men were more often classified as hippocampal sparing AD, whereas limbic predominant AD was more common in women. Men and women did not differ in frequency of MAPT haplotype or APOE genotype. Atypical clinical presentations, younger age at onset and shorter disease duration were more frequent in men, suggesting that the lower reported frequency of AD in men may be due to more frequent atypical clinical presentations not recognized as AD. Our data suggest that neuropathologically diagnosed AD cases have the same frequency of women and men, but their clinical presentations and ages at onset tend to differ.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Autopsy
- Brain
- Female
- Humans
- Male
- Middle Aged
- Neurofibrillary Tangles
- Psychiatric Status Rating Scales
- Sex Characteristics
- Statistics, Nonparametric
Keywords
- Age
- Alzheimer’s disease
- Atypical
- Autopsy
- Gender
- Late onset
- Neurofibrillary tangle
- Neuropathology
- Plaques
- Postmortem
- Sex
- Young onset
Preclinical Alzheimer's disease (AD) is defined by cerebral amyloid-β positivity (Aβ ) in cognitively normal (CN) older adults. To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study. Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aβ , APOEɛ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years. 17.7% Aβ and 8.1% Aβ-progressed over 8 years (OR: 2.43). Risk of progression for Aβ was 65-104% greater than Aβ-. Aβ APOEɛ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aβ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ4 carriage (HR: 2.63); only age was a significant risk factor in Aβ-(HR: 1.09). Aβ-progressors were not near the threshold for Aβ . These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA. Aβ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOEɛ4 carriage provides further predictive value in the presence of Aβ . These data suggest that Aβ-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aβ deposition may be the result of neuropathological processes other than AD that accumulate with age.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Amyloid beta-Peptides
- Apolipoprotein E4
- Cerebral Cortex
- Cognitive Dysfunction
- Dementia
- Disease Progression
- Female
- Humans
- Longitudinal Studies
- Male
- Middle Aged
- Positron-Emission Tomography
- Statistics, Nonparametric
- Survival Analysis
Keywords
- APOEɛ4
- Alzheimer’s disease
- biomarkers
- dementia
- mild cognitive impairment
Lifetime risk factors for cognitive and functional decline in Alzheimer's disease (AD) are not fully understood, and were prospectively evaluated in patients with low mean schooling from São Paulo, Brazil. Consecutive outpatients with late-onset AD were assessed for APOE haplotypes and the following potential baseline predictors: gender, schooling, age at dementia onset, lifetime urban living and sanitary conditions, occupational complexity, cognitive and physical activities, cerebrovascular risk factors (obesity, lifetime alcohol use and smoking, length of arterial hypertension, diabetes mellitus, and a dyslipidemic profile), use of a pacemaker, creatinine clearance, body mass index, waist circumference, head traumas with unconsciousness, treated systemic bacterial infections, amount of surgical procedures under general anesthesia, and family history of AD. Participants were followed from October 2010 to May 2017 for baseline risk factor associations with time since dementia onset for Clinical Dementia Rating and Mini-Mental State Examination score changes. For 227 patients (154 women, 119 APOE ε 4 carriers), later AD onset (mean 73.60±6.4 years-old, earlier for APOE ε 4/ε 4 carriers, p < 0.001) was the only variable hastening all endpoints, baseline creatinine clearance and lifetime alcohol use were hazardous for earlier cognitive and functional endpoints, women had earlier cognitive endpoints only, and schooling had a cumulative protective effect over later cognitive endpoints, particularly for carriers of APOE ε 4. Exclusively for carriers of APOE ε 4, head traumas with unconsciousness were hazardous for earlier cognitive endpoints, while lifetime sanitary conditions were protective regarding later cognitive endpoints. Functional and cognitive outcomes in AD represent probable interactions between effects of brain reserve and cerebral perfusion over neurodegeneration.
MeSH Terms
- Aged
- Aged, 80 and over
- Alzheimer Disease
- Apolipoproteins E
- Brazil
- Cognition Disorders
- Educational Status
- Female
- Humans
- Male
- Neuropsychological Tests
- Outcome Assessment, Health Care
- Proportional Hazards Models
- Retrospective Studies
- Risk Factors
- Time Factors
Keywords
- Aging
- Alzheimer’s disease
- cognition
- dementia
- educational status
- neurodegenerative diseases
- neuropsychiatry
- risk factors
Alzheimer's disease (AD) is an age-associated neurodegenerative disease characterized by amyloidosis, tauopathy, and activation of microglia, the brain resident innate immune cells. We show that a RiboTag translational profiling approach can bypass biases due to cellular enrichment/cell sorting. Using this approach in models of amyloidosis, tauopathy, and aging, we revealed a common set of alterations and identified a central APOE-driven network that converged on CCL3 and CCL4 across all conditions. Notably, aged females demonstrated a significant exacerbation of many of these shared transcripts in this APOE network, revealing a potential mechanism for increased AD susceptibility in females. This study has broad implications for microglial transcriptomic approaches and provides new insights into microglial pathways associated with different pathological aspects of aging and AD.
MeSH Terms
- Aging
- Alzheimer Disease
- Amyloid
- Amyloidosis
- Animals
- Apolipoproteins E
- Chemokine CCL3
- Chemokine CCL4
- Disease Models, Animal
- Female
- Male
- Mice
- Mice, Transgenic
- Microglia
- Signal Transduction
- tau Proteins
The ε4 allele of the APOE gene is associated with poorer cognition in later life. This study aimed to advance understanding of how environments potentially moderate this genetic risk by focusing on childhood socioeconomic status (SES). Previous research across diverse national contexts has found that older adults from higher-SES families in childhood demonstrate better cognitive functioning than their lower-SES counterparts. Nevertheless, few studies have examined whether higher childhood SES might also promote later life cognition by mitigating the effects of ε4 carrier status. To address this gap, we used data from 3017 participants in the Wisconsin Longitudinal Study, which has followed a random sample of people who graduated from Wisconsin high schools in 1957. Childhood SES included parents' educational attainment, father's occupational status, and household income in adolescence. We constructed measures of memory and of language/executive functioning using scores from neurocognitive tests administered when participants were approximately ages 65 and 72. APOE ε4 status was measured through saliva samples. Results from cross-controlled multilevel models indicated that APOE ε4 status-and not childhood SES-independently predicted memory, whereas childhood SES-and not APOE ε4 status-independently predicted language/executive functioning. Moreover, a statistical interaction between APOE ε4 status and childhood SES for memory indicated that at baseline, higher childhood SES protected against the risk of APOE ε4 status, whereas lower childhood SES exacerbated the risk of APOE ε4 status. However, by follow-up, these moderating effects dissipated, and APOE ε4 status alone was associated with memory. We interpret these results in light of theorizing on differential susceptibility for poorer cognition across the life course.
MeSH Terms
- Aged
- Apolipoprotein E4
- Child
- Cognition Disorders
- Executive Function
- Female
- Gene-Environment Interaction
- Genetic Predisposition to Disease
- Humans
- Language
- Longitudinal Studies
- Male
- Memory
- Mental Status and Dementia Tests
- Saliva
- Social Class
- Wisconsin
Keywords
- Apolipoprotein E
- Cognitive aging
- Differential susceptibility
- Gene-by-environment interactions
- Life course perspective
- Socioeconomic status
- U.S.
- Wisconsin longitudinal study
Data from a large autopsy series were analyzed to address questions pertinent to primary age-related tauopathy (PART) and Alzheimer's disease (AD): what factors are associated with increased severity of neurofibrillary degeneration in brains that lack neuritic amyloid plaques?; is there an association between Apolipoprotein E (APOE) alleles and PART pathologic severity independent of amyloid-β (Aβ) deposits?; and, how do the stains used to detect plaques and tangles impact the experimental results? Neuropathologic data were evaluated from elderly research volunteers whose brain autopsies were performed at University of Kentucky Alzheimer's Disease Center (UK-ADC; N = 145 subjects). All of the included subjects' brains lacked neuritic amyloid plaques according to the CERAD diagnostic criteria and the average final MMSE score before death was 26.8±4.6 stdev. The study incorporated evaluation of tissue with both silver histochemical stains and immunohistochemical stains to compare results; the immunohistochemical stains (Aβ and phospho-tau) were scanned and quantified using digital pathologic methods. Immunohistochemical stains provided important advantages over histochemical stains due to sensitivity and detectability via digital methods. When AD-type pathology was in its presumed earliest phases, neocortical parenchymal Aβ deposits were associated with increased medial temporal lobe neurofibrillary tangles. The observation supports the NIA-AA consensus recommendation for neuropathologic diagnoses, because even these "diffuse" Aβ deposits signal that AD pathobiologic mechanisms are occurring. Further, the data were most compatible with the hypothesis that the APOEɛ4 allele exerts its effect(s) via driving Aβ deposition, i.e., an "upstream" influence, rather than being associated directly with Aβ- independent PART pathology.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Amyloid beta-Peptides
- Apolipoproteins E
- Brain
- Female
- Humans
- Male
- Neurofibrillary Tangles
- Plaque, Amyloid
- Silver Staining
- tau Proteins
Keywords
- Aging
- Genie
- MAPT
- SNAP
- ScanScope
- amyloid-β
- hippocampus
- neuropathology
- oldest-old
The role of the innate immune system in Alzheimer's disease (AD) and neurodegenerative disease susceptibility has recently been highlighted in genetic studies. However, we do not know whether risk for inflammatory disease predisposes unaffected individuals to late-life cognitive deficits or AD-related neuropathology. We investigated whether genetic risk scores for seven immune diseases and central nervous system traits were related to cognitive decline (n = 1601), classical AD neuropathology (n = 985), or microglial density (n = 184). Longitudinal cognitive decline, postmortem amyloid and tau neuropathology, microglial density, and gene module expression from bulk brain tissue were all measured in participants from two large cohorts (the Rush Religious Orders Study and Memory and Aging Project; ROS/MAP) of elderly subjects (mean age at entry 78 /- 8.7 years). We analyzed data primarily using robust regression methods. Neuropathologists were blind to clinical data. The AD genetic risk scores, including and excluding APOE effects, were strongly associated with cognitive decline in all domains (min P = 3.2 × 10 ). Multiple sclerosis (MS), Parkinson's disease, and schizophrenia risk did not influence cognitive decline in older age, but the rheumatoid arthritis (RA) risk score alone was significantly associated with microglial density after correction (t = - 3.88, P = 1.6 × 10 ). Post-hoc tests found significant effects of the RA genetic risk score in multiple regions and stages of microglial activation (min P = 1.5 × 10 ). However, these associations were driven by only one or two variants, rather than cumulative polygenicity. Further, individual MS (P < 8.4 × 10 ) and RA (P = 3 × 10 ) variants associated with higher microglial density were also associated with increased expression of brain immune gene modules. Our results demonstrate that global risk of inflammatory disease does not strongly influence aging-related cognitive decline but that susceptibility variants that influence peripheral immune function also alter microglial density and immune gene expression in the aging brain, opening a new perspective on the control of microglial and immune responses within the central nervous system. Further study on the molecular mechanisms of peripheral immune disease risk influencing glial cell activation will be required to identify key regulators of these pathways.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Arthritis, Rheumatoid
- Cognitive Dysfunction
- Female
- Genetic Variation
- Genotype
- Humans
- Inflammation
- Male
- Microglia
- Multifactorial Inheritance
- Multiple Sclerosis
- Parkinson Disease
- Risk Factors
- Schizophrenia
Keywords
- Alzheimer’s disease
- Genomics
- Inflammation
- Innate immunity
- Microglia
- Neuropathology
- Polygenic score
- Postmortem
- RNA sequencing
Dual-task paradigms, in which an individual performs tasks separately and then concurrently, often demonstrate that people with neurodegenerative disorders experience more dual-task interference, defined as worse performance in the dual-task condition compared to the single-task condition. To examine how gait-cognition dual-task performance differs between cognitively normal older adults with and without an APOE ɛ4 allele. Twenty-nine individuals ages 60 to 72 with normal cognition completed a dual-task protocol in which walking and cognitive tasks (executive function, memory) were performed separately and concurrently. Fourteen participants carried APOE ɛ4 alleles (ɛ3/ɛ4 or ɛ2/ɛ4); fifteen had APOE genotypes (ɛ2/ɛ2, ɛ2/ɛ3, or ɛ3/ɛ3) associated with lower risk of Alzheimer's disease (AD). The two risk groups did not differ by age, sex, race, education, or gait or cognitive measures under single-task conditions. Compared to low risk participants, APOE ɛ4 carriers tended to exhibit greater dual-task interference. Both the memory and executive function tasks resulted in dual-task interference on gait, but effect sizes for a group difference were larger when the cognitive task was executive function. In the dual-task protocol that combined walking and the executive function task, effect sizes for group difference in gait interference were larger (0.62- 0.70) than for cognitive interference (0.45- 0.47). Dual-task paradigms may reveal subtle changes in brain function in asymptomatic individuals at heightened risk of AD.
MeSH Terms
- Aged
- Aged, 80 and over
- Alzheimer Disease
- Apolipoprotein E4
- Cognition
- Cohort Studies
- Executive Function
- Female
- Gait
- Humans
- Male
- Memory
- Middle Aged
- Neuropsychological Tests
- Pilot Projects
- Task Performance and Analysis
Keywords
- Aging brain
- cognitive performance
- cognitive reserve
- dementia
- diagnosis
- early detection
- motor interference
- phenotype
- risk
- stress test
{{medline-entry |title=Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults. |pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30018169 |abstract=Mechanisms underlying the association between age-related arterial stiffening and poor brain health remain elusive. Cerebral blood flow (CBF) homeostasis may be implicated. This study evaluates how aortic stiffening relates to resting CBF and cerebrovascular reactivity (CVR) in older adults. Vanderbilt Memory