Back to Search Start Over

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

Authors :
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. De Jager
Reisa A. Sperling
Source :
Nature Communications, Vol 14, Iss 1, Pp 1-13 (2023)
Publication Year :
2023
Publisher :
Nature Portfolio, 2023.

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.

Subjects

Subjects :
Science

Details

Language :
English
ISSN :
20411723
Volume :
14
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.0e512e3890b148e388c778ba58f1e579
Document Type :
article
Full Text :
https://doi.org/10.1038/s41467-023-43132-2