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Title: Genetic risk for Alzheimer’s dementia predicts motor deficits through multi-omic systems in older adults

Abstract

Alzheimer’s disease manifests with both cognitive and motor deficits. However, the degree to which genetic risk of Alzheimer’s dementia contributes to late-life motor impairment, and the specific molecular systems underlying these associations, are uncertain. Here, we adopted an integrative multi-omic approach to assess genetic influence on motor impairment in older adults and identified key molecular pathways that may mediate this risk. We built a polygenic risk score for clinical diagnosis of Alzheimer’s dementia (AD-PRS) and examined its relationship to several motor phenotypes in 1885 older individuals from two longitudinal aging cohorts. We found that AD-PRS was associated with a previously validated composite motor scores and their components. The major genetic risk factor for sporadic Alzheimer’s dementia, the APOE/TOMM40 locus, was not a major driver of these associations. To identify specific molecular features that potentially medicate the genetic risk into motor dysfunction, we examined brain multi-omics, including transcriptome, DNA methylation, histone acetylation (H3K9AC), and targeted proteomics, as well as diverse neuropathologies. We found that a small number of factors account for the majority of the influence of AD-PRS on motor function, which comprises paired helical filament tau-tangle density, H3K9AC in specific chromosomal regions encoding genes involved in neuromuscular process. These multi-omicmore » factors have the potential to elucidate key molecular mechanisms developing motor impairment in the context of Alzheimer’s dementia.« less

Authors:
ORCiD logo [1];  [1]; ORCiD logo [2];  [1]; ORCiD logo [3];  [1];  [1]
  1. Rush Univ. Medical Center, Chicago, IL (United States). Rush Alzheimer's Disease Center, and Dept. of Neurological Sciences
  2. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Biological Sciences Division
  3. Columbia Univ. Medical Center, New York, NY (United States). Center for Translational and Computational Neuroimmunology; Broad Inst., Cambridge, MA (United States). Cell Circuits Program
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1577840
Report Number(s):
PNNL-SA-148783
Journal ID: ISSN 2158-3188
Grant/Contract Number:  
AC05-76RL01830
Resource Type:
Accepted Manuscript
Journal Name:
Translational Psychiatry
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2158-3188
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Tasaki, Shinya, Gaiteri, Chris, Petyuk, Vladislav A., Blizinsky, Katherine D., De Jager, Philip L., Buchman, Aron S., and Bennett, David A. Genetic risk for Alzheimer’s dementia predicts motor deficits through multi-omic systems in older adults. United States: N. p., 2019. Web. doi:10.1038/s41398-019-0577-4.
Tasaki, Shinya, Gaiteri, Chris, Petyuk, Vladislav A., Blizinsky, Katherine D., De Jager, Philip L., Buchman, Aron S., & Bennett, David A. Genetic risk for Alzheimer’s dementia predicts motor deficits through multi-omic systems in older adults. United States. doi:10.1038/s41398-019-0577-4.
Tasaki, Shinya, Gaiteri, Chris, Petyuk, Vladislav A., Blizinsky, Katherine D., De Jager, Philip L., Buchman, Aron S., and Bennett, David A. Thu . "Genetic risk for Alzheimer’s dementia predicts motor deficits through multi-omic systems in older adults". United States. doi:10.1038/s41398-019-0577-4. https://www.osti.gov/servlets/purl/1577840.
@article{osti_1577840,
title = {Genetic risk for Alzheimer’s dementia predicts motor deficits through multi-omic systems in older adults},
author = {Tasaki, Shinya and Gaiteri, Chris and Petyuk, Vladislav A. and Blizinsky, Katherine D. and De Jager, Philip L. and Buchman, Aron S. and Bennett, David A.},
abstractNote = {Alzheimer’s disease manifests with both cognitive and motor deficits. However, the degree to which genetic risk of Alzheimer’s dementia contributes to late-life motor impairment, and the specific molecular systems underlying these associations, are uncertain. Here, we adopted an integrative multi-omic approach to assess genetic influence on motor impairment in older adults and identified key molecular pathways that may mediate this risk. We built a polygenic risk score for clinical diagnosis of Alzheimer’s dementia (AD-PRS) and examined its relationship to several motor phenotypes in 1885 older individuals from two longitudinal aging cohorts. We found that AD-PRS was associated with a previously validated composite motor scores and their components. The major genetic risk factor for sporadic Alzheimer’s dementia, the APOE/TOMM40 locus, was not a major driver of these associations. To identify specific molecular features that potentially medicate the genetic risk into motor dysfunction, we examined brain multi-omics, including transcriptome, DNA methylation, histone acetylation (H3K9AC), and targeted proteomics, as well as diverse neuropathologies. We found that a small number of factors account for the majority of the influence of AD-PRS on motor function, which comprises paired helical filament tau-tangle density, H3K9AC in specific chromosomal regions encoding genes involved in neuromuscular process. These multi-omic factors have the potential to elucidate key molecular mechanisms developing motor impairment in the context of Alzheimer’s dementia.},
doi = {10.1038/s41398-019-0577-4},
journal = {Translational Psychiatry},
number = 1,
volume = 9,
place = {United States},
year = {2019},
month = {10}
}

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