TY - JOUR
T1 - Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets
AU - Neff, Ryan A.
AU - Wang, Minghui
AU - Vatansever, Sezen
AU - Guo, Lei
AU - Ming, Chen
AU - Wang, Qian
AU - Wang, Erming
AU - Horgusluoglu-Moloch, Emrin
AU - Song, Won Min
AU - Li, Aiqun
AU - Castranio, Emilie L.
AU - Julia, T. C.W.
AU - Ho, Lap
AU - Goate, Alison
AU - Fossati, Valentina
AU - Noggle, Scott
AU - Gandy, Sam
AU - Ehrlich, Michelle E.
AU - Katsel, Pavel
AU - Schadt, Eric
AU - Cai, Dongming
AU - Brennand, Kristen J.
AU - Haroutunian, Vahram
AU - Zhang, Bin
N1 - Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved;
PY - 2021/1/6
Y1 - 2021/1/6
N2 - 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 GABRB2, LRP10, MSN, PLP1, and ATP6V1A. 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.
AB - 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 GABRB2, LRP10, MSN, PLP1, and ATP6V1A. 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.
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U2 - 10.1126/sciadv.abb5398
DO - 10.1126/sciadv.abb5398
M3 - Article
C2 - 33523961
AN - SCOPUS:85099251264
SN - 2375-2548
VL - 7
JO - Science Advances
JF - Science Advances
IS - 2
M1 - eabb5398
ER -