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However, the degree to which genetic risk of Alzheimer\u2019s 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\u2019s 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\u2019s dementia, the\n                    <jats:italic>APOE<\/jats:italic>\n                    \/\n                    <jats:italic>TOMM40<\/jats:italic>\n                    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\u2019s dementia.\n                  <\/jats:p>","DOI":"10.1038\/s41398-019-0577-4","type":"journal-article","created":{"date-parts":[[2019,10,3]],"date-time":"2019-10-03T11:05:21Z","timestamp":1570100721000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Genetic risk for Alzheimer\u2019s dementia predicts motor deficits through multi-omic systems in older adults"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3656-7394","authenticated-orcid":false,"given":"Shinya","family":"Tasaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Gaiteri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4076-151X","authenticated-orcid":false,"given":"Vladislav A.","family":"Petyuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine D.","family":"Blizinsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2505","authenticated-orcid":false,"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aron S.","family":"Buchman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,10,3]]},"reference":[{"key":"577_CR1","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1212\/01.wnl.0000324864.81179.6a","volume":"71","author":"AS Buchman","year":"2008","unstructured":"Buchman, A. 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