Examining the Association Between an Endolysosomal Polygenic Risk Score and Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is a highly heritable but polygenic common neurodegenerative disorder. Recent discoveries of AD risk susceptibility loci by genome-wide association studies (GWAS) have small overall effects, and translation of these small effects into accurate personalized risk assessments is challenging. Pathway-specific polygenic risk scores (PRSs) to assess combined effects of multiple genetic variants within specific biological pathways can offer a more precise and accurate prediction of an individual's risk for that trait. We examine the association between an endolysosomal pathway-specific PRS (ePRS) and a general AD PRS with AD case-control status and AD neuropathology in a sample collected by the UW Alzheimer’s Disease Research Center. We conducted expression quantitative trait locus (eQTL) analysis of genes contributing to our ePRS in bulk RNA sequencing from leptomeningeal tissue. ePRS was significantly associated with amyloid beta (Aβ)-related neuropathology and AD case-control status using strict cognitive testing criteria, but not significantly associated with tau-related neuropathology. A general AD PRS showed smaller effects on each AD phenotype than the ePRS. eQTL analysis of ePRS genes in leptomeningeal fibroblasts did not show an association between effect allele count and gene count beyond rs3764650 and ABCA7, although these results could change with a larger sample size. Together, our results suggest a pathway-specific PRS could assist in risk prediction and aid in interpretation of neuropathological changes that occur due to polygenic AD risk.