Featured ArticleGenetic epistasis regulates amyloid deposition in resilient aging

•Brain-derived neurotrophic factor (BDNF) Val66Met interacts with SORL1 variants to impact expression of SORL1-005.•SORL1-005 may influence diffuse rather than neuritic amyloid pathology in postmortem brain.•The BDNF-SORL1 interaction effect is present in individuals without confirmed Alzheimer's disease.•In vivo amyloid, measured by positron emission tomography imaging, is also impacted by the BDNF-SORL1 interaction.

IntroductionThe 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.MethodsWe 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.ResultsWe found one SORL1 RNA transcript strongly regulated by SORL1-BDNF interactions in elderly without pathological AD and showing stronger associations with diffuse than neuritic Aβ plaques. The same SORL1-BDNF interactions also significantly influenced Aβ load as measured with [18F]Florbetapir positron emission tomography.DiscussionOur results bridge the gap between risk and resilience factors for AD, demonstrating interdependent roles of established SORL1 and BDNF functional genotypes.