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 »
- Authors:
-
[1];
[2];
[3];
- Rush Univ. Medical Center, Chicago, IL (United States). Rush Alzheimer's Disease Center, and Dept. of Neurological Sciences
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Biological Sciences Division
- 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 Laboratory (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. https://doi.org/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. https://doi.org/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 = {Thu Oct 03 00:00:00 EDT 2019},
month = {Thu Oct 03 00:00:00 EDT 2019}
}
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