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Genetic epistasis regulates amyloid deposition in resilient aging.

ABSTRACT: INTRODUCTION:The brain-derived neurotrophic factor (BDNF) interacts with important genetic Alzheimer's disease (AD) risk factors. Specifically, variants within the SORL1 gene determine BDNF's ability to reduce amyloid ? (A?) in vitro. We sought to test whether functional BDNF variation interacts with SORL1 genotypes to influence expression and downstream AD-related processes in humans. METHODS:We analyzed postmortem brain RNA sequencing and neuropathological data for 441 subjects from the Religious Orders Study/Memory and Aging Project and molecular and structural neuroimaging data for 1285 subjects from the Alzheimer's Disease Neuroimaging Initiative. RESULTS:We found one SORL1 RNA transcript strongly regulated by SORL1-BDNF interactions in elderly without pathological AD and showing stronger associations with diffuse than neuritic A? plaques. The same SORL1-BDNF interactions also significantly influenced A? load as measured with [18F]Florbetapir positron emission tomography. DISCUSSION:Our results bridge the gap between risk and resilience factors for AD, demonstrating interdependent roles of established SORL1 and BDNF functional genotypes.

SUBMITTER: Felsky D

PROVIDER: S-EPMC5601013 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Genetic epistasis regulates amyloid deposition in resilient aging.

Felsky Daniel D Xu Jishu J Chibnik Lori B LB Schneider Julie A JA Knight Jo J Kennedy James L JL Bennett David A DA De Jager Philip L PL Voineskos Aristotle N AN

Alzheimer's & dementia : the journal of the Alzheimer's Association 20170317 10

<h4>Introduction</h4>The brain-derived neurotrophic factor (BDNF) interacts with important genetic Alzheimer's disease (AD) risk factors. Specifically, variants within the SORL1 gene determine BDNF's ability to reduce amyloid β (Aβ) in vitro. We sought to test whether functional BDNF variation interacts with SORL1 genotypes to influence expression and downstream AD-related processes in humans.<h4>Methods</h4>We analyzed postmortem brain RNA sequencing and neuropathological data for 441 subjects ...[more]

PMID: 28322202

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Project description:Current approaches to the early detection of Alzheimer's disease (AD) rely upon classifying individuals as "positive" or "negative" for biomarkers related to the core pathology of ?-amyloid (A?). However, the accumulation of A? begins slowly, years before biomarkers become abnormal. We used longitudinal [11C] Pittsburgh Compound B PET scanning and neuropsychological assessment to investigate the earliest changes in AD pathology and how it affects memory in cognitively normal older humans (N = 71; mean age 75 years; 35% male). We used [18F] AV-1451 PET scanning at the end of the observation period to measure subsequent tau deposition in a subset of our sample (N = 37). We found evidence for an inverted-U relationship between baseline A? levels and A? slope in asymptomatic older adults, suggesting a slowing of A? accumulation even in cognitively normal adults. In participants who were nominally amyloid negative, both the rate of amyloid accumulation and the baseline levels of A? predicted early tau deposition in cortical Braak regions associated with AD. Amyloid measures were only sensitive to memory decline as baseline levels of A? increased, suggesting that pathological accumulation occurs before impacting memory. These findings support the necessity of early intervention with amyloid-lowering therapies even in those who are amyloid negative.SIGNIFICANCE STATEMENT The progressive nature of Alzheimer's disease (AD) necessitates the earliest possible detection of pathological or cognitive change if disease progression is to be slowed. We examined cognitively normal older adults in whom AD pathology is starting to develop, with the goal of early detection of AD pathology or cognitive changes. We found amyloid measures to be sensitive early on in predicting subsequent early tau deposition. Further, it appears that rates of amyloid accumulation already begin to slow in preclinical AD, suggesting that it is a relatively late stage of AD progression. Thus, it is crucial to examine older adults early, before amyloid levels have saturated, to intervene to slow disease progression.

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Genetic epistasis regulates amyloid deposition in resilient aging.

Publications

Genetic epistasis regulates amyloid deposition in resilient aging.

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