Population Attributable Risk in Alzheimer and Parkinson Diseases

ObjectivesEmerging evidence suggests that the genetic architecture of Alzheimer disease (AD) and Parkinson disease (PD) risk varies across ancestries. This study seeks to explore distinct and universal genetic targets across individuals of Latino, African/African-admixed, East Asian, and European populations by implementing population attributable risk (PAR) comparisons using summary statistics from genome-wide association studies (GWASs). MethodsPAR was calculated for the most significant disease variants using summary statistics derived from select multi-ancestry GWAS meta-analyses, followed by fine-mapping analysis to validate genetic contribution of disease variants to European, African/African-admixed, East Asian, and Latino individuals. ResultsFor AD, APOE4 PAR estimates were universally high across all ancestries, with TSPAN14 and PICALM emerging as other common targets. Attributable risk varied across PD-related major risk loci, including variation nearby GBA1 and LRRK2. By contrast, SNCA, MCCC1, VPS13C, and MAPT loci demonstrated comparable attributable risk across ancestries. DiscussionThis cross-ancestry evaluation of PAR reinforces the genetic heterogeneity of AD and PD. In consideration of the complex etiology of these diseases, these findings may inform the strategic prioritization of therapeutic targets and improve global health outcomes.