Genetic risk for Alzheimer's dementia predicts motor deficits through multi-omic systems in older adults.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
03 10 2019
03 10 2019
Historique:
received:
15
01
2019
accepted:
24
05
2019
entrez:
5
10
2019
pubmed:
5
10
2019
medline:
17
7
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31582723
doi: 10.1038/s41398-019-0577-4
pii: 10.1038/s41398-019-0577-4
pmc: PMC6776503
doi:
Substances chimiques
H3-3A protein, human
0
Histones
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
241Subventions
Organisme : NIA NIH HHS
ID : U01 AG046152
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG056352
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG017917
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG010161
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG059732
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG015819
Pays : United States
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