Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease.
medRxiv
; 2023 Jun 05.
Article
en En
| MEDLINE
| ID: mdl-37333223
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 Aß plaques, while microglial (Mic) ADPRS was associated with neuritic Aß 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 Aß, and Mic-ADPRS was associated with Aß 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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
MedRxiv
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos