Genetic epistasis regulates amyloid deposition in resilient aging. Issue 10 (16th March 2017) - Felsky, Daniel
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 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. 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 Aβ plaques. The same SORL1 ‐ BDNF interactions also significantly influenced Aβ load as measured with [ 18 F]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. Highlights: 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.