INTRODUCTION: An integrative polygenic risk score (iPRS) capturing the neurodegenerative and vascular contribution to dementia could identify high-risk individuals and improve risk prediction. METHODS: We developed an iPRS for dementia (iPRS-DEM) in Europeans (aged 65+), comprising genetic risk for Alzheimer's disease (AD) and 23 vascular or neurodegenerative traits (excluding apolipoprotein E [APOE]). iPRS-DEM was evaluated across cohorts comprising older community-dwelling people (N = 3702), a multi-ancestry biobank (N = 130,797 Europeans
105,404 non-Europeans), and dementia-free memory clinic participants (N = 2032). RESULTS: iPRS-DEM was associated with dementia risk independently of APOE in the elderly (subdistribution hazard ratio [sHR] DISCUSSION: Alongside APOE ε4, iPRS-DEM may refine risk stratification for the enrichment of dementia clinical trials and prevention programs. HIGHLIGHTS: iPRS-DEM reflects neurodegenerative and vascular contribution to dementia. We show iPRS-DEM captures additional dementia genetic risk beyond APOE and AD-PRS. iPRS-DEM, in combination with APOE ε4, shows promise for dementia risk stratification. Our results generalize across both population-based and memory-clinic settings. We show transportability of iPRS-DEM to East Asian ancestry.