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 De Jager; Reisa A Sperling

doi:10.1101/2023.06.01.23290850

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

medRxiv [Preprint]. 2023 Jun 5:2023.06.01.23290850. doi: 10.1101/2023.06.01.23290850.

Authors

Hyun-Sik Yang^{1

2

3

4}, Ling Teng^{1

4}, Daniel Kang², Vilas Menon⁵, Tian Ge^{3

4

6}, Hilary K Finucane^{3

4

7}, Aaron P Schultz^{2

3}, Michael Properzi², Hans-Ulrich Klein⁵, Lori B Chibnik^{2

4

8}, Julie A Schneider⁹, David A Bennett⁹, Timothy J Hohman¹⁰, Richard P Mayeux⁵, Keith A Johnson^{1

2

3

11}, Philip L De Jager⁵, Reisa A Sperling^{1

2

3}

Affiliations

¹ Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
² Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
³ Harvard Medical School, Boston, MA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA.
⁵ Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
⁶ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
¹⁰ Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹ Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.

Abstract

Alzheimer's disease (AD) heritability is enriched in glial genes, but how and when cell-type-specific genetic risk contributes to AD remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets. In an autopsy dataset spanning all stages of AD (n=1,457), astrocytic (Ast) ADPRS was associated with both diffuse and neuritic Aβ plaques, while microglial (Mic) ADPRS was associated with neuritic Aβ plaques, microglial activation, tau, and cognitive decline. Causal modeling analyses further clarified these relationships. In an independent neuroimaging dataset of cognitively unimpaired elderly (n=2,921), Ast-ADPRS were associated with Aβ, and Mic-ADPRS was associated with Aβ and tau, showing a consistent pattern with the autopsy dataset. Oligodendrocytic and excitatory neuronal ADPRSs were associated with tau, but only in the autopsy dataset including symptomatic AD cases. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage.

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Preprint

Abstract

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