Unified epigenomic, transcriptomic, proteomic, and metabolomic taxonomy of Alzheimer’s disease progression and heterogeneity

Iturria-Medina, Yasser; Adewale, Quadri; Khan, Ahmed F.; Ducharme, Simon; Rosa-Neto, Pedro; O’Donnell, Kieran; Petyuk, Vladislav A.; Gauthier, Serge; De Jager, Philip L.; Breitner, John; Bennett, David A.

doi:10.1126/sciadv.abo6764

Unified epigenomic, transcriptomic, proteomic, and metabolomic taxonomy of Alzheimer’s disease progression and heterogeneity

Journal Article · Fri Nov 18 00:00:00 EST 2022 · Science Advances

DOI:https://doi.org/10.1126/sciadv.abo6764· OSTI ID:2471580

^[1]; ^[1]; Khan, Ahmed F. ^[1]; ^[2]; ^[3]; O’Donnell, Kieran ^[4]; ^[5]; Gauthier, Serge ^[3]; ^[6]; ^[7]; ^[8]

Montreal Neurological Institute (Canada); Ludmer Centre for Neuroinformatics and Mental Health, Montreal (Canada)
Montreal Neurological Institute (Canada); McGill Univ., Montreal, QC (Canada)
McGill Univ., Montreal, QC (Canada)
Ludmer Centre for Neuroinformatics and Mental Health, Montreal (Canada); Yale Univ., New Haven, CT (United States)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Columbia Univ., New York, NY (United States)
Douglas Research Centre, Montreal QC (Canada); McGill Univ., Montreal, QC (Canada)
Rush University Medical Center, Chicago, IL (United States)

Alzheimer’s disease (AD) is a heterogeneous disorder with abnormalities in multiple biological domains. In an advanced machine learning analysis of postmortem brain and in vivo blood multi-omics molecular data (N= 1863), we integrated epigenomic, transcriptomic, proteomic, and metabolomic profiles into a multilevel biological AD taxonomy. We obtained a personalized multilevel molecular index of AD dementia progression that predicts severity of neuropathologies, and identified three robust molecular-based subtypes that explain much of the pathologic and clinical heterogeneity of AD. These subtypes present distinct patterns of alteration in DNA methylation, RNA, proteins, and metabolites, identifiable in the brain and subsequently in blood. In addition, the genetic variations that predispose to the various AD subtypes in brain predict distinct spatial patterns of alteration in cell types, suggesting a unique influence of each putative AD variant on neuropathological mechanisms. These observations support that an individually tailored multi-omics molecular taxonomy of AD may represent distinct targets for preventive or treatment interventions.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2471580

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 46 Vol. 8; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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