Cell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease

Author:

Yang Hyun-SikORCID,Teng Ling,Kang Daniel,Menon VilasORCID,Ge Tian,Finucane Hilary K.ORCID,Schultz Aaron P.,Properzi Michael,Klein Hans-UlrichORCID,Chibnik Lori B.ORCID,Schneider Julie A.ORCID,Bennett David A.,Hohman Timothy J.ORCID,Mayeux Richard P.,Johnson Keith A.,De Jager Philip L.ORCID,Sperling Reisa A.ORCID

Abstract

AbstractMany of the Alzheimer’s disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how and when the genetic risk localizing to these cell types contributes to AD pathophysiology remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets and uncover the impact of cell-type-specific genetic risk on AD endophenotypes. In an autopsy dataset spanning all stages of AD (n = 1457), the astrocytic ADPRS affected diffuse and neuritic plaques (amyloid-β), while microglial ADPRS affected neuritic plaques, microglial activation, neurofibrillary tangles (tau), and cognitive decline. In an independent neuroimaging dataset of cognitively unimpaired elderly (n = 2921), astrocytic ADPRS was associated with amyloid-β, and microglial ADPRS was associated with amyloid-β and tau, connecting cell-type-specific genetic risk with AD pathology even before symptom onset. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage.

Funder

U.S. Department of Health & Human Services | NIH | National Institute on Aging

Eli Lilly and Company

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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