October 3, 2019
Journal Article

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-omic factors have the potential to elucidate key molecular mechanisms developing motor impairment in the context of Alzheimer’s dementia.

Revised: February 15, 2021 | Published: October 3, 2019

Citation

Tasaki S., C. Gaiteri, V.A. Petyuk, K.D. Blizinsky, P.L. De Jager, A. Buchman, and D.A. Bennett. 2019. "Genetic risk for Alzheimer's dementia predicts motor deficits through multi-omic systems in older adults." Translational Psychiatry 9. PNNL-SA-148783. doi:10.1038/s41398-019-0577-4