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
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Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Genetic epistasis regulates amyloid deposition in resilient aging
AU - Felsky, Daniel
AU - Xu, Jishu
AU - Chibnik, Lori
AU - Schneider, Julie
AU - Knight, Jo
AU - Kennedy, James L.
AU - Bennett, David A.
AU - De Jager, Philip L.
AU - Voineskos, Aristotle N.
N1 - 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
PY - 2017/10
Y1 - 2017/10
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Epistasis
KW - RNA sequencing
KW - Amyloid
KW - BDNF
KW - SORL1
KW - PET imaging
U2 - 10.1016/j.jalz.2017.01.027
DO - 10.1016/j.jalz.2017.01.027
M3 - Journal article
VL - 13
SP - 1107
EP - 1116
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
SN - 1552-5260
IS - 10
ER -