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

Hyun-Sik Yang (), Ling Teng, Daniel Kang, Vilas Menon, Tian Ge, Hilary K. Finucane, Aaron P. Schultz, Michael Properzi, Hans-Ulrich Klein, Lori B. Chibnik, Julie A. Schneider, David A. Bennett, Timothy J. Hohman, Richard P. Mayeux, Keith A. Johnson, Philip L. Jager and Reisa A. Sperling
Additional contact information
Hyun-Sik Yang: Brigham and Women’s Hospital
Ling Teng: Brigham and Women’s Hospital
Daniel Kang: Massachusetts General Hospital
Vilas Menon: Columbia University Irving Medical Center
Tian Ge: Harvard Medical School
Hilary K. Finucane: Harvard Medical School
Aaron P. Schultz: Massachusetts General Hospital
Michael Properzi: Massachusetts General Hospital
Hans-Ulrich Klein: Columbia University Irving Medical Center
Lori B. Chibnik: Massachusetts General Hospital
Julie A. Schneider: Rush University Medical Center
David A. Bennett: Rush University Medical Center
Timothy J. Hohman: Vanderbilt University Medical Center
Richard P. Mayeux: Columbia University Irving Medical Center
Keith A. Johnson: Brigham and Women’s Hospital
Philip L. Jager: Columbia University Irving Medical Center
Reisa A. Sperling: Brigham and Women’s Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Many 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.

Date: 2023
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DOI: 10.1038/s41467-023-43132-2

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