Population-specific polygenic risk for Alzheimer's disease is associated with Mini-Mental State Examination-based cognitive decline in a Japanese cohort

Alzheimer's disease (AD) is a major cause of dementia, with polygenic risk scores (PRSs) widely used to capture cumulative genetic risk. While PRSs have been associated with cognitive decline, their relevance to clinically accessible measures in general populations is not yet fully established, particularly in non-European cohorts. In this study, we investigated the association between AD PRSs and cognitive function assessed by the Mini-Mental State Examination (MMSE) in a community-dwelling Japanese older population (N = 1,301). Three PRSs were constructed using genome-wide association study (GWAS) summary statistics derived from European and Japanese populations. Among the PRSs, the score based on Japanese GWAS showed the strongest and most consistent association with MMSE score, whereas those based on European GWAS showed weaker or no associations. Stratification analyses further demonstrated that individuals with higher PRS exhibited lower MMSE scores and a higher prevalence of cognitive impairment. Notably, these associations were attenuated after excluding participants with dementia, suggesting that PRS primarily reflects clinically relevant cognitive decline. No significant associations were observed between PRSs and hippocampal volume in our cohort. These findings highlight the importance of population-specific PRS and suggest its potential utility for stratifying cognitive impairment using simple clinical measures in community-based settings.