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Genetic epistasis regulates amyloid deposition in resilient aging

descriptionPublicationkeyboard_double_arrow_right Article 16 Mar 2017 United Kingdom English Publisher:WileyJournal:Alzheimer's & Dementia, volume 13, pages 1,107-1,116 (issn: 1552-5260, eissn: 1552-5279,

Copyright policy )Funded by:NIH | Epidemiologic Study of Ne..., NIH | Mechanisms linking insuli..., NIH | SHORT-TERM STABILITY OF C... +5 projects

Authors: Lori B. Chibnik; Lori B. Chibnik; Daniel Felsky; Philip L. De Jager; Philip L. De Jager; Jo Knight; Jo Knight; +9 Authors

doi: 10.1016/j.jalz.2017.01.027

pmid: 28322202

pmc: PMC5601013

Genetic epistasis regulates amyloid deposition in resilient aging

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Abstract

AbstractIntroductionThe 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.

Country

United Kingdom

Related Organizations

University of Toronto
Canada
Brigham and Women's Faulkner Hospital
United States
Lancaster University
United Kingdom
Broad Institute
United States
Rush University Medical Center
United States

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Keywords

Male, Aging, Genotype, 610, Cohort Studies, Alzheimer Disease, 616, Humans, Genetic Predisposition to Disease, LDL-Receptor Related Proteins, Aged, Aged, 80 and over, Amyloid beta-Peptides, Aniline Compounds, Brain-Derived Neurotrophic Factor, Brain, Epistasis, Genetic, Magnetic Resonance Imaging, Anisotropy, Ethylene Glycols, Female, Autopsy

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