Title | Molecular subtyping of Alzheimer's disease using RNA sequencing data reveals novel mechanisms and targets. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Neff RA, Wang M, Vatansever S, Guo L, Ming C, Wang Q, Wang E, Horgusluoglu-Moloch E, Song W-M, Li A, Castranio EL, Tcw J, Ho L, Goate A, Fossati V, Noggle S, Gandy S, Ehrlich ME, Katsel P, Schadt E, Cai D, Brennand KJ, Haroutunian V, Zhang B |
Journal | Sci Adv |
Volume | 7 |
Issue | 2 |
Date Published | 2021 Jan |
ISSN | 2375-2548 |
Abstract | Alzheimer's disease (AD), the most common form of dementia, is recognized as a heterogeneous disease with diverse pathophysiologic mechanisms. In this study, we interrogate the molecular heterogeneity of AD by analyzing 1543 transcriptomes across five brain regions in two AD cohorts using an integrative network approach. We identify three major molecular subtypes of AD corresponding to different combinations of multiple dysregulated pathways, such as susceptibility to tau-mediated neurodegeneration, amyloid-β neuroinflammation, synaptic signaling, immune activity, mitochondria organization, and myelination. Multiscale network analysis reveals subtype-specific drivers such as , , , , and We further demonstrate that variations between existing AD mouse models recapitulate a certain degree of subtype heterogeneity, which may partially explain why a vast majority of drugs that succeeded in specific mouse models do not align with generalized human trials across all AD subtypes. Therefore, subtyping patients with AD is a critical step toward precision medicine for this devastating disease. |
DOI | 10.1126/sciadv.abb5398 |
Pubmed Link | https://www.ncbi.nlm.nih.gov/pubmed/33523961?dopt=Abstract |
page_expo | Internal |
Alternate Journal | Sci Adv |
PubMed ID | 33523961 |
PubMed Central ID | PMC7787497 |
Grant List | U01 AG046152 / AG / NIA NIH HHS / United States RF1 AG054014 / AG / NIA NIH HHS / United States R01 AG017917 / AG / NIA NIH HHS / United States RF1 AG059319 / AG / NIA NIH HHS / United States R01 AG068030 / AG / NIA NIH HHS / United States T32 GM007280 / GM / NIGMS NIH HHS / United States U01 AG058635 / AG / NIA NIH HHS / United States P30 AG066514 / AG / NIA NIH HHS / United States U01 AG052411 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States R01 AG030146 / AG / NIA NIH HHS / United States U01 AG046170 / AG / NIA NIH HHS / United States R01 AG057907 / AG / NIA NIH HHS / United States P30 AG010161 / AG / NIA NIH HHS / United States R56 AG058655 / AG / NIA NIH HHS / United States R01 AG062355 / AG / NIA NIH HHS / United States R01 AG036836 / AG / NIA NIH HHS / United States R01 AG015819 / AG / NIA NIH HHS / United States |
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