September 29, 2021

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

Hyun-Sik Yang, MD

Additional Authors: Daniel Kang, AB; Vilas Menon, PhD; Hans-Ulrich Klein, PhD; Tian Ge, PhD; Hilary Finucane, PhD; Lori B. Chibnik, PhD; Timothy J. Hohman, PhD; Richard P Mayeux, MD; Philip L De Jager, MD, PhD; Reisa A. Sperling, MD

Background: Conventional polygenic risk score (PRS) summarizes genetic risk throughout the genome and lacks biological specificity. Here, leveraging human brain single nucleus RNA sequencing (sNuc-Seq) data, we introduce a new method to capture cell-type specific Alzheimer’s disease (AD) PRS, and implicate different cell types in distinct disease processes in preclinical AD.

Method: Cognitively unimpaired (CU) older adults of European descent who participated in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study screening PET were included in this study. Cortical amyloid-β burden (Aβ) was quantified as cortical composite SUVR from the florbetapir PET. Screening cognition was measured with Preclinical Alzheimer Cognitive Composite (PACC). We defined cell type-specific genes as genes expressed higher in a given cell type (FDR

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