Редактирование: MAPT

Microtubule-associated protein tau (Neurofibrillary tangle protein) (Paired helical filament-tau) (PHF-tau) [MAPTL] [MTBT1] [TAU]

==Publications==

{{medline-entry
|title=Association of relative brain age with tobacco smoking, alcohol consumption, and genetic variants.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32001736
|abstract=Brain age is a metric that quantifies the degree of aging of a brain based on whole-brain anatomical characteristics. While associations between individual human brain regions and environmental or genetic factors have been investigated, how brain age is associated with those factors remains unclear. We investigated these associations using UK Biobank data. We first trained a statistical model for obtaining relative brain age (RBA), a metric describing a subject's brain age relative to peers, based on whole-brain anatomical measurements, from training set subjects (n = 5,193). We then applied this model to evaluation set subjects (n = 12,115) and tested the association of RBA with tobacco smoking, alcohol consumption, and genetic variants. We found that daily or almost daily consumption of tobacco and alcohol were both significantly associated with increased RBA (P < 0.001). We also found SNPs significantly associated with RBA (p-value < 5E-8). The SNP most significantly associated with RBA is located in [[MAPT]] gene. Our results suggest that both environmental and genetic factors are associated with structural brain aging.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alcohol Drinking
* Biological Specimen Banks
* Brain
* Cognition
* Female
* Humans
* Magnetic Resonance Imaging
* Male
* Middle Aged
* Neuroimaging
* Polymorphism, Single Nucleotide
* Smoking
* United Kingdom
* tau Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992742
}}
{{medline-entry
|title=A blood-based nutritional risk index explains cognitive enhancement and decline in the multidomain Alzheimer prevention trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31921969
|abstract=Multinutrient approaches may produce more robust effects on brain health through interactive qualities. We hypothesized that a blood-based nutritional risk index (NRI) including three biomarkers of diet quality can explain cognitive trajectories in the multidomain Alzheimer prevention trial ([[MAPT]]) over 3-years. The NRI included erythrocyte n-3 polyunsaturated fatty acids (n-3 PUFA 22:6n-3 and 20:5n-3), serum 25-hydroxyvitamin D, and plasma homocysteine. The NRI scores reflect the number of nutritional risk factors (0-3). The primary outcome in [[MAPT]] was a cognitive composite [i]Z[/i] score within each participant that was fit with linear mixed-effects models. Eighty percent had at lease one nutritional risk factor for cognitive decline (NRI ≥1: 573 of 712). Participants presenting without nutritional risk factors (NRI=0) exhibited cognitive enhancement ([i]β[/i] = 0.03 standard units [SU]/y), whereas each NRI point increase corresponded to an incremental acceleration in rates of cognitive decline (NRI-1: [i]β[/i] = -0.04 SU/y, [i]P[/i] = .03; NRI-2: [i]β[/i] = -0.08 SU/y, [i]P[/i] < .0001; and NRI-3: [i]β[/i] = -0.11 SU/y, [i]P[/i] = .0008). Identifying and addressing these well-established nutritional risk factors may reduce age-related cognitive decline in older adults; an observation that warrants further study.

|keywords=* Aging
* Biomarkers of diet quality
* Cognitive decline
* DHA
* EPA
* Elderly
* Homocysteine
* Metabolomics
* Nutrient biomarkers
* Omega-3 fatty acids
* Vitamin D
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944714
}}
{{medline-entry
|title=Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31733664
|abstract=Alzheimer's disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that nondependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, two-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins [[MAPT]] (Tau), amyloid beta precursor protein ([[APP]]), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, [[HK1]], [[AK1]], [[PGAM1]], CKB), cytoskeletal development (BASP1, [[CAP1]], [[DPYSL2]] [CRMP2], [[ALDOA]], [[TUBA1A]], [[CFL2]], ACTG1), cellular/oxidative stress (HSPA5, [[HSPA8]], [[ENO1]], ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human [[MAPT]], [[APP]], and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wild-type mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol-free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex, medial prefrontal cortex, and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late-stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer's pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, [[IRS1]], [[IGF1R]], [[PTEN]], ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.
|mesh-terms=* Alcohol Drinking
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Behavior, Animal
* Brain
* Disease Models, Animal
* Mice, Transgenic
* tau Proteins
|keywords=* Aging
* Amyloid beta
* Ethanol
* GSK
* Immunohistochemistry
* Morris Water Maze
* Prepulse inhibition
* Self-administration
* Tau pathology
* Transgenic mouse model
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939615
}}
{{medline-entry
|title=Longitudinal associations of physical activity levels with morphological and functional changes related with aging: The [[MAPT]] study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31669813
|abstract=The biological process of aging is characterized by molecular and physiological processes that lead to alterations in the organism. There is still a lack of a consensus about the measurement of biological aging, but physical activity (PA) could be a potential marker of an aging phenotype. Measurements of body composition, muscle quality (MQ), blood biochemistry, and neurodegeneration were assessed over three years. Physical activity levels were measured using a self-reported questionnaire. Three-year progression of PA levels showed that those who maintained low levels of PA was significantly associated with the evolution of brain and hippocampal volume, compared to inactive individuals. Similar results were found always active individuals, but also had better cognition. PA levels are associated with some elements of biological aging, but more studies with objective-based PA measurements could provide a more in-depth knowledge on biological aging.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Body Composition
* Brain
* Cognition
* Exercise
* Female
* Humans
* Longitudinal Studies
* Male
|keywords=* Aging
* Biomarkers
* Phenotype
* Physical activity
|full-text-url=https://sci-hub.do/10.1016/j.exger.2019.110758
}}
{{medline-entry
|title=Ageing and amyloidosis underlie the molecular and pathological alterations of tau in a mouse model of familial Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31673052
|abstract=Despite compelling evidence that the accumulation of amyloid-beta (Aβ) promotes neocortical [[MAPT]] (tau) aggregation in familial and idiopathic Alzheimer's disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. In the present study, we show that tau can accumulate spontaneously in aged transgenic [[APP]] /PS1  mice. Tau pathology is abundant around Aβ deposits, and further characterized by accumulation of Gallyas and thioflavin-S-positive inclusions, which were detected in the [[APP]] /PS1  brain at 18 months of age. Age-dependent increases in argyrophilia correlated positively with binding levels of the paired helical filament (PHF) tracer [ F]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Quantitative proteomics identified sequences of hyperphosphorylated and three-repeat tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Tissue from the frontal gyrus of human subjects was used to validate these findings, revealing primarily quantitative differences between the tau pathology observed in AD patient vs. transgenic mouse tissue. As physiological levels of endogenous, 'wild-type' tau aggregate secondarily to Aβ in [[APP]] /PS1  mice, this study suggests that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloidosis
* Animals
* Disease Models, Animal
* Mice
* Mice, Transgenic
* tau Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823454
}}
{{medline-entry
|title=Revisiting the intersection of amyloid, pathologically modified tau and iron in Alzheimer's disease from a ferroptosis perspective.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31604111
|abstract=The complexity of Alzheimer's disease (AD) complicates the search for effective treatments. While the key roles of pathologically modified proteins has occupied a central role in hypotheses of the pathophysiology, less attention has been paid to the potential role for transition metals overload, subsequent oxidative stress, and tissue injury. The association of transition metals, the major focus heretofore iron and amyloid, the same can now be said for the likely pathogenic microtubular associated tau ([[MAPT]]). This review discusses the interplay between iron, pathologically modified tau and oxidative stress, and connects many related discoveries. Basic principles of the transition to pathological [[MAPT]] are discussed. Iron, its homeostatic mechanisms, the recently described phenomenon of ferroptosis and purported, although still controversial roles in AD are reviewed as well as considerations to overcome existing hurdles of iron-targeted therapeutic avenues that have been attempted in AD. We summarize the involvement of multiple pathological pathways at different disease stages of disease progression that supports the potential for a combinatorial treatment strategy targeting multiple factors.

|keywords=* Alzheimer’s disease
* Ferroptosis
* Iron
* Reactive oxygen species
* Senescence
* Tau
|full-text-url=https://sci-hub.do/10.1016/j.pneurobio.2019.101716
}}
{{medline-entry
|title=Factors associated with changes of the frailty status after age 70: Findings in the [[MAPT]] study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31005551
|abstract=Frailty has become a major issue in the prevention of functional decline and disability in aged populations. Using repeated measurements of frailty over 3 years, this work aimed to describe transitions between frailty states and associated factors. This study used the data from the Multidomain Alzheimer Preventive Trial and included the 842 participants aged 70 and over who did not receive the multidomain intervention. Frailty was assessed using the phenotype proposed by Fried et al. at baseline and at 6, 12, 24, and 36 months. Factors influencing the transitions across frailty states were examined using multistate modeling. The study population included 548 women and 294 men, mean age 75.4 ± 4.5 years. At baseline, 430 (53%) participants were nonfrail, 349 (43%) prefrail, and 28 (4%) frail. A total of 2271 pairs of consecutive measurements of frailty status were available over the 3 years of follow-up, with no change in frailty status in 1548 of them (68%), a worsening of frailty status in 426 of them (19%), and an improvement in frailty status in the remaining 297 (13%). Polypharmacy (i.e., ≥6 drugs) and probable depression were associated with incident prefrailty. Female gender was systematically associated with a lower probability of recovering from prefrailty and frailty. Older age, overweight, comorbidity, and abnormal C-reactive protein also reduced the probability of recovery from frailty or prefrailty. This study sheds light on factors that should be further investigated in future research to help the prevention and management of frailty.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Body Mass Index
* Cognitive Dysfunction
* Depression
* Exercise Test
* Female
* Frail Elderly
* Frailty
* Geriatric Assessment
* Hand Strength
* Humans
* Male
* Muscle Strength
* Polypharmacy
* Walk Test
* Walking Speed
|keywords=* Depression
* Frail elderly
* Gender
* Polypharmacy
* Predictors
* Transitions
|full-text-url=https://sci-hub.do/10.1016/j.annepidem.2019.03.008
}}
{{medline-entry
|title=Mitophagy and NAD  inhibit Alzheimer disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30922179
|abstract=Our latest publication on the inhibition of Alzheimer disease (AD) through mitophagy consolidates the 'defective mitophagy hypothesis of AD etiology'. Dementia (majorly AD) affects over 50 million people worldwide, and for AD there is no cure. AD leads to progressive loss of cognition, and pathological hallmarks of AD include aggregates of amyloid-β peptides extracellularly and [[MAPT]] (microtubule associated protein tau) intracellularly. However, there is no conclusive link between these pathological markers and cognitive symptoms. Anti-AD drug candidates have repeatedly failed, which led us to investigate other molecular etiologies to guide drug development. Mitochondria produce the majority of cellular ATP, affect Ca  and redox signaling, and promote developmental and synaptic plasticity. Mitochondrial dysfunction and accumulation of damaged mitochondria are common in brain tissues from AD patients and transgenic AD animal models, but the underlying molecular mechanisms are not fully understood. Damaged mitochondria are removed through multiple pathways, the major 2 being mitophagy and the ubiquitin proteasome pathway. Mitophagy is essential for clearance of damaged mitochondria to maintain mitochondrial homeostasis, ATP production, and neuronal activity and survival. These pieces of evidence converge on the 'defective mitophagy hypothesis of AD etiology', and the current cross-species study provides strong support for this hypothesis.
|mesh-terms=* Alzheimer Disease
* Animals
* Autophagy
* Cognition
* Humans
* Mitophagy
* NAD
|keywords=* Alzheimer’s disease
* Mitophagy
* aging
* memory
* mitochondria
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526831
}}
{{medline-entry
|title=Cognitive changes of older adults with an equivocal amyloid load.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30689016
|abstract=Observational and interventional studies addressing the link between amyloid (Aβ) burden and cognitive decline are increasing, but a clear definition of amyloid positivity is still lacking. This may represent a great stake for therapeutic studies enrolling Aβ   patients only. The main objective of this study was to define a population with "equivocal" amyloid status, and evaluate their cognitive changes. Sixty-five participants over 75 years old, from the Control group of the interventional [[MAPT]] study, at risk to develop Alzheimer's disease, were included. Participants were classified into three groups in terms of amyloid load: Aβ  , Aβ - and Equivocal participants (according to visual reading, global standardized uptake (SUVR) cut-offs, or a k-mean clustering method). The cognitive changes over time (memory, executive functions, attention and processing speed) of this Equivocal group were then compared to Aβ   and Aβ - participants. When classified by visual read, Equivocal participants' memory scores were comparable to the Aβ- participants, and greater than in Aβ   participants over time. Secondary analyses, using SUVR cut-offs classification, showed different trajectories with Equivocal participants being comparable to the Aβ   participants, and lower than Aβ-, on executive performance over time. This original work pointed out a population that may be of great interest for interventional studies, raising the question of how amyloid status should be defined and integrated in such studies. These findings should be replicated in future studies on larger datasets, to confirm what methodological approach would be the most suitable to highlight this specific neuroimaging entity.
|mesh-terms=* Aged
* Aging
* Amyloid
* Aniline Compounds
* Brain
* Cognition
* Cognitive Dysfunction
* Ethylene Glycols
* Executive Function
* Female
* Follow-Up Studies
* Humans
* Male
* Memory
* Neuropsychological Tests
* Positron-Emission Tomography
* Radiopharmaceuticals
|keywords=* Amyloid imaging
* Equivocal cases
* Executive functions
* Memory
|full-text-url=https://sci-hub.do/10.1007/s00415-019-09203-5
}}
{{medline-entry
|title=Tauopathy: A common mechanism for neurodegeneration and brain aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30668956
|abstract=Tau, a microtubule-associated protein promotes assembly and stability of microtubules which is related to axoplasmic flow and critical neuronal activities upon physiological conditions. Under neurodegenerative condition such as in Alzheimer's Disease (AD), tau-microtubule binding dynamics and equilibrium are severely affected due to its aberrant post-translational modifications including acetylation and hyperphosphorylation. This event results in its conformational changes to form neurofibrillary tangles (NFT) after aggregation in the cytosol. The formation of NFT is more strongly correlated with cognitive decline than the distribution of senile plaque, which is formed by polymorphous beta-amyloid (Aβ) protein deposits, another pathological hallmark of AD. In neurodegenerative conditions, other than AD, the disease manifestation is correlated with mutations of the [[MAPT]] gene. In Primary age-related tauopathy (PART), which is commonly observed in the brains of aged individuals, tau deposition is directly correlated with cognitive deficits even in the absence of Aβ deposition. Thus, tauopathy has been considered as an essential hallmark in neurodegeneration and normal brain aging. In this review, we highlighted the recent progress about the tauopathies in the light of its posttranslational modifications and its implication in AD and the aged brain.
|mesh-terms=* Acetylation
* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Brain
* Cognitive Dysfunction
* Humans
* Neurofibrillary Tangles
* Oxidative Stress
* Phosphorylation
* Plaque, Amyloid
* Protein Processing, Post-Translational
* Tauopathies
* tau Proteins
|keywords=* Aging
* Alzheimer’s disease
* Amyloid beta
* Cognitive dysfunction
* Neurodegeneration
* Tau acetylation
* Tau hyperphosphorylation
* Tauopathy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377302
}}
{{medline-entry
|title=Cinnamaldehyde Improves Lifespan and Healthspan in [i]Drosophila melanogaster[/i] Models for Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30228985
|abstract=Cinnamon extract has been reported to have positive effects in fruit fly and mouse models for Alzheimer's disease (AD). However, cinnamon contains numerous potential active compounds that have not been individually evaluated. The main objective of this study was to evaluate the impact of cinnamaldehyde, a known putative active compound in cinnamon, on the lifespan and healthspan of [i]Drosophila melanogaster[/i] models for Alzheimer's disease, which overexpress A[i]β[/i]  and [[MAPT]] (Tau). We found that cinnamaldehyde significantly improved the lifespan of both AD and non-AD flies. Cinnamaldehyde also improved the healthspan of AD flies overexpressing the Tau protein by improving climbing ability, evaluated by rapid iterative negative geotaxis (RING), and improving short-term memory, evaluated by a courtship conditioning assay. Cinnamaldehyde had no positive impact on the healthspan of AD flies overexpressing the A[i]β[/i]  protein.
|mesh-terms=* Acrolein
* Alzheimer Disease
* Animals
* Disease Models, Animal
* Drosophila melanogaster
* Longevity
* tau Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136480
}}
{{medline-entry
|title=Sex and age interact to determine clinicopathologic differences in Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30219939
|abstract=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
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280837
}}
{{medline-entry
|title=Effects of a 3-Year Multi-Domain Intervention with or without Omega-3 Supplementation on Cognitive Functions in Older Subjects with Increased CAIDE Dementia Scores.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29865075
|abstract=Findings from recent Alzheimer's disease prevention trials have shown subjects with increased dementia score based upon mid-life cardiovascular risk factors, to benefit from multi-domain intervention strategies to some extent. The effects of such interventions on cognitive functions remains yet to be well-established. This study is a secondary analysis of the [[MAPT]] study, 1,293 older subjects (mean age 75 years) with high CAIDE score (i.e., ≥6) were classified according to the four intervention groups: 1) multi-domain intervention plus placebo, 2) isolated supplementation with Omega-3 polyunsaturated fatty acid (n-3 PUFA), 3) combination of the two interventions, and 4) placebo alone. Linear mixed-model repeated-measures analyses were used to assess the cognitive changes according to various neuropsychological test scores between intervention groups compared to the placebo at 36 months from baseline. Compared to the placebo, group with multi-domain intervention in combination withn-3PUFA was found to show significant improvement in the delayed total recall test of the free and cued selective reminding test (FCSRT) (mean±standard error(SE) = 0.20±0.10) and MMSE orientation test (mean±SE = 0.15±0.06) at 36 months. Isolated multi-domain intervention group showed significant less decline in the MMSE orientation test (mean±SE = 0.12±0.06) compared to the placebo. There was significant less improvement (mean±SE = - 1.01±0.46) in the FCSRT free recall test in the n-3 PUFA intervention group compared to the placebo at 36 months. Our findings show high-risk subjects for dementia screened with CAIDE dementia score might benefit from multi-domain intervention strategies as in the [[MAPT]] study, particularly in the orientation and delayed recall domain.
|mesh-terms=* Activities of Daily Living
* Aged
* Aged, 80 and over
* Aging
* Cognition
* Dementia
* Dietary Supplements
* Fatty Acids, Omega-3
* Female
* Humans
* Longitudinal Studies
* Male
* Neuropsychological Tests
* Psychiatric Status Rating Scales
|keywords=* Alzheimer’s disease
* CAIDE
* MAPT study
* cognitive decline
* cognitive functions
* multi-domain intervention
* n-3 PUFA
* neuropsychological tests
* omega-3
* prevention
|full-text-url=https://sci-hub.do/10.3233/JAD-180209
}}
{{medline-entry
|title=Whole-Exome Sequencing of an Exceptional Longevity Cohort.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29750252
|abstract=Centenarians represent a unique cohort to study the genetic basis for longevity and factors determining the risk of neurodegenerative disorders, including Alzheimer's disease (AD). The estimated genetic contribution to longevity is highest in centenarians and super-cententenarians, but few genetic variants have been shown to clearly impact this phenotype. While the genetic risk for AD and other dementias is now well understood, the frequency of known dementia risk variants in centenarians is not fully characterized. To address these questions, we performed whole-exome sequencing on 100 individuals of 98-108 years age in search of genes with large effect sizes towards the exceptional aging phenotype. Overall, we were unable to identify a rare protein-altering variant or individual genes with an increased burden of rare variants associated with exceptional longevity. Gene burden analysis revealed three genes of nominal statistical significance associated with extreme aging, including [[LYST]], [[MDN1]], and [[RBMXL1]]. Several genes with variants conferring an increased risk for AD and other dementias were identified, including [[TREM2]], [[EPHA1]], [[ABCA7]], [[PLD3]], [[MAPT]], and [[NOTCH3]]. Larger centenarian studies will be required to further elucidate the genetic basis for longevity, and factors conferring protection against age-dependent neurodegenerative syndromes.
|mesh-terms=* Age Factors
* Aged, 80 and over
* Alzheimer Disease
* Cohort Studies
* Dementia
* Female
* Humans
* Longevity
* Male
* Risk Factors
* Whole Exome Sequencing
|keywords=* Alzheimer’s disease
* Centenarian
* Dementia
* SKAT
* Whole-exome sequencing
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696723
}}
{{medline-entry
|title=Interaction between a [[MAPT]] variant causing frontotemporal dementia and mutant [[APP]] affects axonal transport.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29729423
|abstract=In Alzheimer's disease, many indicators point to a central role for poor axonal transport, but the potential for stimulating axonal transport to alleviate the disease remains largely untested. Previously, we reported enhanced anterograde axonal transport of mitochondria in 8- to 11-month-old [[MAPT]]  knockin mice, a genetic model of frontotemporal dementia with parkinsonism-17T. In this study, we further characterized the axonal transport of mitochondria in younger [[MAPT]]  mice crossed with the familial Alzheimer's disease model, TgCRND8, aiming to test whether boosting axonal transport in young TgCRND8 mice can alleviate axonal swelling. We successfully replicated the enhancement of anterograde axonal transport in young [[MAPT]]  knockin animals. Surprisingly, we found that in the presence of the amyloid precursor protein mutations, [[MAPT]]  impaired anterograde axonal transport. The numbers of plaque-associated axonal swellings or amyloid plaques in TgCRND8 brains were unaltered. These findings suggest that amyloid-β promotes an action of mutant tau that impairs axonal transport. As amyloid-β levels increase with age even without amyloid precursor protein mutation, we suggest that this rise could contribute to age-related decline in frontotemporal dementia.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Axonal Transport
* Brain
* Disease Models, Animal
* Frontotemporal Dementia
* Genetic Association Studies
* Genetic Variation
* Male
* Mice, Inbred C57BL
* Mice, Transgenic
* Mitochondria
* Mutation
* Plaque, Amyloid
* tau Proteins
|keywords=* Alzheimer's disease
* Axonal transport
* Aβ
* FTDP-17T
* Mitochondria
* P301L mutation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998378
}}
{{medline-entry
|title=Evaluating the Patterns of Aging-Related Tau Astrogliopathy Unravels Novel Insights Into Brain Aging and Neurodegenerative Diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28340083
|abstract=The term "aging-related tau astrogliopathy" (ARTAG) describes pathological accumulation of abnormally phosphorylated tau protein in astrocytes. We evaluated the correlates of ARTAG types (i.e., subpial, subependymal, white and gray matter, and perivascular) in different neuroanatomical regions. Clinical, neuropathological, and genetic (eg, [[APOE]] ε4 allele, [[MAPT]] H1/H2 haplotype) data from 628 postmortem brains from subjects were investigated; most of the patients had been longitudinally followed at the University of Pennsylvania. We found that (i) the amygdala is a hotspot for all ARTAG types; (ii) age at death, male sex, and presence of primary frontotemporal lobar degeneration (FTLD) tauopathy are significantly associated with ARTAG; (iii) age at death, greater degree of brain atrophy, ventricular enlargement, and Alzheimer disease (AD)-related variables are associated with subpial, white matter, and perivascular ARTAG types; (iv) AD-related variables are associated particularly with lobar white matter ARTAG; and (v) gray matter ARTAG in primary FTLD-tauopathies appears in areas without neuronal tau pathology. We provide a reference map of ARTAG types and propose at least 5 constellations of ARTAG. Furthermore, we propose a conceptual link between primary FTLD-tauopathy and ARTAG-related astrocytic tau pathologies. Our observations serve as a basis for etiological stratification and definition of progression patterns of ARTAG.
|mesh-terms=* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Apolipoproteins E
* Astrocytes
* Atrophy
* Brain
* Female
* Frontotemporal Lobar Degeneration
* Humans
* Longitudinal Studies
* Male
* Neurodegenerative Diseases
* Neuroglia
* Sex Factors
* Tauopathies
* tau Proteins
|keywords=* ARTAG
* Aging-related tau astrogliopathy
* Alzheimer disease
* Chronic traumatic encephalopathy
* Dementia
* Tau
* Tauopathy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251691
}}
{{medline-entry
|title=CSF protein changes associated with hippocampal sclerosis risk gene variants highlight impact of [[GRN]]/P[[GRN]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28189700
|abstract=Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs). Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): [[GRN]] (rs5848), [[TMEM106B]] (rs1990622), [[ABCC9]] (rs704180), and [[KCNMB2]] (rs9637454). For controls, non-HS-Aging SNPs in [[APOE]] (rs429358/rs7412) and [[MAPT]] (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes. The [[GRN]] risk SNP (rs5848) status correlated with variation in CSF proteins, with the risk allele (T) associated with increased levels of [[AXL]] Receptor Tyrosine Kinase ([[AXL]]), [[TNF]]-Related Apoptosis-Inducing Ligand Receptor 3 (TRAIL-R3), Vascular Cell Adhesion Molecule-1 (VCAM-1) and clusterin (CLU) (all p<0.05 after Bonferroni correction). The TRAIL-R3 correlation was significant in meta-analysis with an additional dataset (p=5.05×10 ). Further, the rs5848 SNP status was associated with increased CSF tau protein - a marker of neurodegeneration (p=0.015). These data are remarkable since this [[GRN]] SNP has been found to be a risk factor for multiple types of dementia-related brain pathologies.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Amyloid beta-Peptides
* Biomarkers
* Clusterin
* Databases, Factual
* Dementia
* Female
* GPI-Linked Proteins
* Genetic Predisposition to Disease
* Genome-Wide Association Study
* Hippocampus
* Humans
* Intercellular Signaling Peptides and Proteins
* Male
* Polymorphism, Single Nucleotide
* Progranulins
* Receptors, Tumor Necrosis Factor, Member 10c
* Regression Analysis
* Risk Factors
* Sclerosis
* Vascular Cell Adhesion Molecule-1
* tau Proteins
|keywords=* Biomarkers
* Clusterin
* Granulin
* Neuroinflammation
* Progranulin
* Proteomics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389672
}}
{{medline-entry
|title=Koolen-de Vries Syndrome: Clinical Report of an Adult and Literature Review.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27852077
|abstract=Koolen-de Vries syndrome (KdS) is a rare genetic condition characterized by typical facial dysmorphisms, cardiac and renal defects, skeletal anomalies, developmental delay, and intellectual disability of variable level. It is caused by a 440-680-kb deletion in the 17q21.31 region, encompassing [[CRHR1]], [[MAPT]], IMP5, [[STH]], and [[KANSL1]], or by an intragenic [[KANSL1]] mutation. The majority of the patients reported are pediatric or young adults, and long-term studies able to define the prognosis of the disease are lacking. Here, we report a patient in the fourth decade misdiagnosed in the past as classical Ehlers-Danlos syndrome for the presence of generalized joint hypermobility, who carried a 546-kb deletion in 17q21.31, and compare his phenotype with those of the few KdS adults (aged >18 years) described so far. We observed a favorable prognosis of epilepsy and cardiovascular signs and reduction of joint hypermobility with age, thus providing insight into the natural history of the disorder.
|mesh-terms=* Abnormalities, Multiple
* Adolescent
* Adult
* Aging
* Child
* Chromosome Deletion
* Chromosomes, Human, Pair 17
* Delayed Diagnosis
* Developmental Disabilities
* Diagnostic Errors
* Ehlers-Danlos Syndrome
* Epilepsy
* Female
* Humans
* Intellectual Disability
* Male
* Middle Aged
* Phenotype
* Prognosis
* Young Adult

|full-text-url=https://sci-hub.do/10.1159/000452724
}}
{{medline-entry
|title=Presymptomatic cognitive decline in familial frontotemporal dementia: A longitudinal study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27358337
|abstract=In this prospective cohort study, we performed a 2-year follow-up study with neuropsychological assessment in the presymptomatic phase of familial frontotemporal dementia (FTD) due to [[GRN]] and [[MAPT]] mutations to explore the prognostic value of neuropsychological assessment in the earliest FTD disease stages. Healthy, at-risk, first-degree relatives of patients with FTD who had a [[MAPT]] (n = 13) or [[GRN]] mutation (n = 30) and healthy controls (n = 39) underwent neuropsychological assessment at baseline and 2-year follow-up. We investigated baseline and longitudinal differences, as well as relationship with age and estimated years before symptom onset. At baseline, [[GRN]] mutation carriers showed lower scores on mental processing speed than healthy controls (p = 0.043). Two years later, [[MAPT]] mutation carriers showed a steeper decline than [[GRN]] mutation carriers on social cognition (p = 0.002). Older age was related to cognitive decline in visuoconstruction (p = 0.005) and social cognition (p = 0.026) in [[MAPT]]. Memory significantly declined from 8 to 6 years before estimated symptom onset in [[MAPT]] and [[GRN]] mutation carriers, respectively, and language and social cognition declined only in [[MAPT]] mutation carriers from 7 to 5 years before estimated symptom onset, respectively (p < 0.05). Using longitudinal neuropsychological assessment, we detected gene-specific neuropsychological patterns of decline in, e.g., social cognition, memory, and visuoconstruction. Our results confirm the prognostic value of neuropsychological assessment as a potential clinical biomarker in the presymptomatic phase of familial FTD.
|mesh-terms=* Adult
* Age of Onset
* Aging
* Cognition Disorders
* Disease Progression
* Female
* Follow-Up Studies
* Frontotemporal Dementia
* Humans
* Intercellular Signaling Peptides and Proteins
* Longitudinal Studies
* Male
* Middle Aged
* Mutation
* Neuropsychological Tests
* Progranulins
* Prospective Studies
* Social Behavior
* tau Proteins

|full-text-url=https://sci-hub.do/10.1212/WNL.0000000000002895
}}
{{medline-entry
|title=Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26912063
|abstract=In frontotemporal dementia (FTD) there is a critical lack in the understanding of biological and molecular mechanisms involved in disease pathogenesis. The heterogeneous genetic features associated with FTD suggest that multiple disease-mechanisms are likely to contribute to the development of this neurodegenerative condition. We here present a systems biology approach with the scope of i) shedding light on the biological processes potentially implicated in the pathogenesis of FTD and ii) identifying novel potential risk factors for FTD. We performed a gene co-expression network analysis of microarray expression data from 101 individuals without neurodegenerative diseases to explore regional-specific co-expression patterns in the frontal and temporal cortices for 12 genes ([[MAPT]], [[GRN]], [[CHMP2B]], [[CTSC]], [[HLA-DRA]], [[TMEM106B]], [[C9orf72]], [[VCP]], [[UBQLN2]], [[OPTN]], [[TARDBP]] and FUS) associated with FTD and we then carried out gene set enrichment and pathway analyses, and investigated known protein-protein interactors (PPIs) of FTD-genes products. Gene co-expression networks revealed that several FTD-genes (such as [[MAPT]] and [[GRN]], [[CTSC]] and [[HLA-DRA]], [[TMEM106B]], and [[C9orf72]], [[VCP]], [[UBQLN2]] and [[OPTN]]) were clustering in modules of relevance in the frontal and temporal cortices. Functional annotation and pathway analyses of such modules indicated enrichment for: i) DNA metabolism, i.e. transcription regulation, DNA protection and chromatin remodelling ([[MAPT]] and [[GRN]] modules); ii) immune and lysosomal processes ([[CTSC]] and [[HLA-DRA]] modules), and; iii) protein meta/catabolism ([[C9orf72]], [[VCP]], [[UBQLN2]] and [[OPTN]], and [[TMEM106B]] modules). PPI analysis supported the results of the functional annotation and pathway analyses. This work further characterizes known FTD-genes and elaborates on their biological relevance to disease: not only do we indicate likely impacted regional-specific biological processes driven by FTD-genes containing modules, but also do we suggest novel potential risk factors among the FTD-genes interactors as targets for further mechanistic characterization in hypothesis driven cell biology work.
|mesh-terms=* Aging
* Animals
* Brain Mapping
* Frontotemporal Dementia
* Gene Regulatory Networks
* Genetic Predisposition to Disease
* Intercellular Signaling Peptides and Proteins
* Mutation
* Risk Factors
* tau Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765225
}}
{{medline-entry
|title=Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26756400
|abstract=Abnormal tau accumulations were observed and documented in post-mortem brains of patients affected by Alzheimer's disease (AD) long before the identification of mutations in the Microtubule-associated protein tau ([[MAPT]]) gene, encoding the tau protein, in a different neurodegenerative disease called Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The discovery of mutations in the [[MAPT]] gene associated with FTDP-17 highlighted that dysfunctions in tau alone are sufficient to cause neurodegeneration. Invertebrate models have been diligently utilized in investigating tauopathies, contributing to the understanding of cellular and molecular pathways involved in disease etiology. An important discovery came with the demonstration that over-expression of human tau in Drosophila leads to premature mortality and neuronal dysfunction including neurodegeneration, recapitulating some key neuropathological features of the human disease. The simplicity of handling invertebrate models combined with the availability of a diverse range of experimental resources make these models, in particular Drosophila a powerful invertebrate screening tool. Consequently, several large-scale screens have been performed using Drosophila, to identify modifiers of tau toxicity. The screens have revealed not only common cellular and molecular pathways, but in some instances the same modifier has been independently identified in two or more screens suggesting a possible role for these modifiers in regulating tau toxicity. The purpose of this review is to discuss the genetic modifier screens on tauopathies performed in Drosophila and C. elegans models, and to highlight the common cellular and molecular pathways that have emerged from these studies. Here, we summarize results of tau toxicity screens providing mechanistic insights into pathological alterations in tauopathies. Key pathways or modifiers that have been identified are associated with a broad range of processes including, but not limited to, phosphorylation, cytoskeleton organization, axonal transport, regulation of cellular proteostasis, transcription, RNA metabolism, cell cycle regulation, and apoptosis. We discuss the utility and application of invertebrate models in elucidating the cellular and molecular functions of novel and uncharacterized disease modifiers identified in large-scale screens as well as for investigating the function of genes identified as risk factors in genome-wide association studies from human patients in the post-genomic era. In this review, we combined and summarized several large-scale modifier screens performed in invertebrate models to identify modifiers of tau toxicity. A summary of the screens show that diverse cellular processes are implicated in the modification of tau toxicity. Kinases and phosphatases are the most predominant class of modifiers followed by components required for cellular proteostasis and axonal transport and cytoskeleton elements. 
|mesh-terms=* Animals
* Animals, Genetically Modified
* Apoptosis
* Axonal Transport
* Caenorhabditis elegans
* Cell Cycle
* Cytoskeleton
* Disease Models, Animal
* Drosophila melanogaster
* Gene Expression Regulation
* Humans
* Invertebrates
* Longevity
* Metabolic Networks and Pathways
* Mice
* Mice, Knockout
* Mutation
* Nerve Degeneration
* Phosphorylation
* Protein Processing, Post-Translational
* Recombinant Fusion Proteins
* Tauopathies
* Zebrafish
* tau Proteins
|keywords=* C. elegans
* Drosophila
* Tau
* genome-wide association studies
* modifier screen
* neurodegeneration
|full-text-url=https://sci-hub.do/10.1111/jnc.13532
}}
{{medline-entry
|title=Drosophila models of Alzheimer's disease: advances, limits, and perspectives.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25697708
|abstract=Amyloid-β protein precursor (AβPP) and the microtubule-associated protein tau ([[MAPT]]) are the two key players involved in Alzheimer's disease (AD) and are associated with amyloid plaques and neurofibrillary tangles respectively, two key hallmarks of the disease. Besides vertebrate models, Drosophila models have been widely used to understand the complex events leading to AD in relation to aging. Drosophila benefits from the low redundancy of the genome which greatly simplifies the analysis of single gene disruption, sophisticated molecular genetic tools, and reduced cost compared to mammals. The aim of this review is to describe the recent advances in modeling AD using fly and to emphasize some limits of these models. Genetic studies in Drosophila have revealed some key aspects of the normal function of Appl and Tau, the fly homologues of AβPP and [[MAPT]] that may be disrupted during AD. Drosophila models have also been useful to uncover or validate several pathological pathways or susceptibility genes, and have been readily implemented in drug screening pipelines. We discuss some limitations of the current models that may arise from differences in structure of Appl and Tau compared to their human counterparts or from missing AβPP or [[MAPT]] protein interactors in flies. The advent of new genome modification technologies should allow the development of more realistic fly models and to better understand the relationship between AD and aging, taking advantage of the fly's short lifespan. 
|mesh-terms=* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Animals, Genetically Modified
* Brain
* Disease Models, Animal
* Drosophila
* Humans
* tau Proteins
|keywords=* Aging
* Alzheimer's disease
* Drosophila
* amyloid beta-peptides
* amyloid beta-protein precursor
* disease models
* nerve degeneration
* tau proteins
* tauopathy
|full-text-url=https://sci-hub.do/10.3233/JAD-142802
}}
{{medline-entry
|title=Association between [[MAPT]] haplotype and memory function in patients with Parkinson's disease and healthy aging individuals.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25577413
|abstract=Genetic variation is associated with differences in the function of the brain as well as its susceptibility to disease. The common H1 haplotypic variant of the microtubule-associated protein tau gene ([[MAPT]]) has been related to an increased risk for Parkinson's disease (PD). Furthermore, among PD patients, H1 homozygotes have an accelerated progression to dementia. We investigated the neurocognitive correlates of [[MAPT]] haplotypes using functional magnetic resonance imaging. Thirty-seven nondemented patients with PD (19 H1/H1, 18 H2 carriers) and 40 age-matched controls (21 H1/H1, 19 H2 carriers) were scanned during performance of a picture memory encoding task. Behaviorally, H1 homozygosity was associated with impaired picture recognition memory in PD patients and control subjects. These impairments in the H1 homozygotes were accompanied by an altered blood-oxygen level-dependent response in the medial temporal lobe during successful memory encoding. Additional age-related differences in blood-oxygen level-dependent response were observed in the medial temporal lobes of H1 homozygotes with PD. These results suggest that common variation in [[MAPT]] is not only associated with the dementia of PD but also differences in the neural circuitry underlying aspects of cognition in normal aging. 
|mesh-terms=* Aged
* Aging
* Cognition
* Disease Progression
* Female
* Genetic Association Studies
* Genetic Predisposition to Disease
* Haplotypes
* Humans
* Magnetic Resonance Imaging
* Male
* Memory
* Middle Aged
* Oxygen
* Parkinson Disease
* Risk
* Temporal Lobe
* tau Proteins
|keywords=* Aging
* Cognitive impairment
* Dementia
* Genetics
* Hippocampus
* MAPT
* Memory
* Parkinson's disease
* Picture recognition
* Tau
* fMRI
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353560
}}
{{medline-entry
|title=Nodes and biological processes identified on the basis of network analysis in the brain of the senescence accelerated mice as an Alzheimer's disease animal model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24194717
|abstract=Harboring the behavioral and histopathological signatures of Alzheimer's disease (AD), senescence accelerated mouse-prone 8 (SAMP8) mice are currently considered a robust model for studying AD. However, the underlying mechanisms, prioritized pathways and genes in SAMP8 mice linked to AD remain unclear. In this study, we provide a biological interpretation of the molecular underpinnings of SAMP8 mice. Our results were derived from differentially expressed genes in the hippocampus and cerebral cortex of SAMP8 mice compared to age-matched SAMR1 mice at 2, 6, and 12 months of age using cDNA microarray analysis. On the basis of PPI, MetaCore and the co-expression network, we constructed a distinct genetic sub-network in the brains of SAMP8 mice. Next, we determined that the regulation of synaptic transmission and apoptosis were disrupted in the brains of SAMP8 mice. We found abnormal gene expression of [[RAF1]], [[MAPT]], [[PTGS2]], [[[[CDKN2A]]]], [[CAMK2A]], [[NTRK2]], [[AGER]], ADRBK1, [[MCM3AP]], and [[STUB1]], which may have initiated the dysfunction of biological processes in the brains of SAMP8 mice. Specifically, we found microRNAs, including miR-20a, miR-17, miR-34a, miR-155, miR-18a, miR-22, miR-26a, miR-101, miR-106b, and miR-125b, that might regulate the expression of nodes in the sub-network. Taken together, these results provide new insights into the biological and genetic mechanisms of SAMP8 mice and add an important dimension to our understanding of the neuro-pathogenesis in SAMP8 mice from a systems perspective. 

|keywords=* Alzheimer's disease
* apoptosis
* cerebral cortex
* differential expressed genes
* hippocampus
* molecular network
* senescence accelerated mouse prone 8
* synaptic transmission
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810591
}}