Journal Article

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

Schneider, Julie A., Finucane, Hilary K., Sperling, Reisa A., Bennett, David A., Mayeux, Richard P., Chibnik, Lori B., Teng, Ling, Properzi, Michael, Johnson, Keith A., Hohman, Timothy J., Schultz, Aaron P., Kang, Daniel, Ge, Tian, Klein, Hans-Ulrich, Menon, Vilas, Yang, Hyun-Sik, De Jager, Philip L.

2023

Overview

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. Alzheimer’s disease genetic risk is enriched in glial genes. Here, the authors derive cell-type-specific polygenic risk scores and link astrocytic genes with Aβ, and microglial genes with Aβ, tau, microglial activation, and cognitive decline.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/43 / 59/57 / 59/78 / 631/208/212/2166 / 631/378/1689/1283 / 631/378/2596/1308 / 631/378/2596/1953 / Aged / Alzheimer Disease - metabolism / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Astrocytes / Autopsies / Autopsy / Cognitive ability / Datasets / Genes / Glial cells / Health risk assessment / Health risks / Humanities and Social Sciences / Humans / Medical imaging / Microglia / multidisciplinary / Neurodegenerative diseases / Neurofibrillary tangles / Neurofibrillary Tangles - genetics / Neurofibrillary Tangles - metabolism / Neuroimaging / Pathophysiology / Plaque, Amyloid - metabolism / Polygenic inheritance / Risk / Risk Factors / Science / Science (multidisciplinary) / Senile plaques / Tau protein / tau Proteins - genetics / tau Proteins - metabolism / β-Amyloid