Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets

Ryan A. Neff, Minghui Wang, Sezen Vatansever, Lei Guo, Chen Ming, Qian Wang, Erming Wang, Emrin Horgusluoglu-Moloch, Won Min Song, Aiqun Li, Emilie L. Castranio, T. C.W. Julia, Lap Ho, Alison Goate, Valentina Fossati, Scott Noggle, Sam Gandy, Michelle E. Ehrlich, Pavel Katsel, Eric SchadtDongming Cai, Kristen J. Brennand, Vahram Haroutunian, Bin Zhang

Research output: Contribution to journalArticlepeer-review

83 Scopus citations


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.

Original languageEnglish
Article numbereabb5398
JournalScience advances
Issue number2
StatePublished - 6 Jan 2021


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