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.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This work was funded by the United States National Institutes of Health (K23AG062750 [H.-S.Y.]). ROSMAP is supported by NIH grants P30AG010161 [D.A.B.], P30AG072975 [D.A.B.], R01AG015819 [D.A.B.], R01AG017917 [D.A.B], U01AG046152 [P.L.D, D.A.B], and U01AG061356 [P.L.D, D.A.B]. The A4 study (NCT02008357) was funded by the National Institute on Aging (grants U19AG010483 [R.A.S. and others] and R01AG063689 [R.A.S. and others]), Eli Lilly and Co, and several philanthropic organizations.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The Institutional Review Board (IRB) of Rush University Medical Center gave ethical approval for this work (secondary use of the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP) data). The IRBs of all participating sites for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study (67 sites in the United States, Australia, Canada, and Japan; details available at https://clinicaltrials.gov/ct2/show/NCT02008357) gave ethical approval for this work (secondary use of the A4 study data).
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Data Availability
ROSMAP resources can be requested at https://www.radc.rush.edu. The A4/LEARN screening (pre-randomization) data can be requested at https://ida.loni.usc.edu/.