Abstract
INTRODUCTION: Genome-wide association studies (GWAS) have identified 80+ genetic loci associated with Alzheimer's disease (AD), enabling the development of polygenic risk scores (PRS). However, the predictive accuracy of PRS in diverse populations remains low. Here, we evaluated the predictive accuracy of single-, multi-, and cross-ancestry AD-PRS models across multi-ancestral populations. METHODS: We used AD GWAS summary statistics from European, African, Amerindian, and East Asian populations to construct AD-PRS for each target population. Model performance was assessed by estimating odds ratios, R(2), and AUC. RESULTS: The cross-ancestry Bayesian PRS model demonstrated the highest predictive performance in non-European populations. It was significantly associated with poorer cognitive function, lower Aβ(42) CSF levels, and the most severe category of Aβ and tau neuropathological burden, as well as a clinical AD latent variable in a multi-ancestral validation cohort. DISCUSSION: Inclusive genetic datasets and cross-ancestry PRS models are needed to enhance the transportability of AD-PRS across multi-ancestral populations.