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  • ADJ-D-16-00588R2-2

    Rights statement: This is the author’s version of a work that was accepted for publication in Alzheimer's & Dementia. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Alzheimer's & Dementia, 13, (10), 2017 DOI: 10.1016/j.jalz.2017.01.027

    Accepted author manuscript, 3.6 MB, PDF document

    Available under license: CC BY-NC-ND: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License

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Genetic epistasis regulates amyloid deposition in resilient aging

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Published
  • Daniel Felsky
  • Jishu Xu
  • Lori Chibnik
  • Julie Schneider
  • Jo Knight
  • James L. Kennedy
  • David A. Bennett
  • Philip L. De Jager
  • Aristotle N. Voineskos
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<mark>Journal publication date</mark>10/2017
<mark>Journal</mark>Alzheimer's and Dementia
Issue number10
Volume13
Number of pages10
Pages (from-to)1107-1116
Publication StatusPublished
Early online date17/03/17
<mark>Original language</mark>English

Abstract

AbstractIntroduction 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 [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.

Bibliographic note

This is the author’s version of a work that was accepted for publication in Alzheimer's & Dementia. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Alzheimer's & Dementia, 13, (10), 2017 DOI: 10.1016/j.jalz.2017.01.027