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Genetic epistasis regulates amyloid deposition in resilient aging

Felsky, Daniel and Xu, Jishu and Chibnik, Lori and Schneider, Julie and Knight, Jo and Kennedy, James L. and Bennett, David A. and De Jager, Philip L. and Voineskos, Aristotle N. (2017) Genetic epistasis regulates amyloid deposition in resilient aging. Alzheimer's and Dementia, 13 (10). pp. 1107-1116. ISSN 1552-5260

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    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.

    Item Type: Journal Article
    Journal or Publication Title: Alzheimer's and Dementia
    Additional Information: 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
    Subjects: ?? ALZHEIMER'S DISEASEEPISTASISRNA SEQUENCINGAMYLOIDBDNFSORL1PET IMAGING ??
    Departments: Faculty of Health and Medicine > Medicine
    ID Code: 85674
    Deposited By: ep_importer_pure
    Deposited On: 24 Mar 2017 11:46
    Refereed?: Yes
    Published?: Published
    Last Modified: 30 Apr 2019 02:34
    Identification Number:
    URI: http://eprints.lancs.ac.uk/id/eprint/85674

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