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