Abstract / Summary
Alzheimer’s disease (AD) is a genetically complex disorder in which inherited susceptibility is distributed across rare high-impact variants, the apolipoprotein E (APOE) locus, and a broad polygenic background of common risk alleles. Polygenic risk scores (PRSs) provide a quantitative framework for summarizing this distributed genetic liability and have become increasingly important tools for risk stratification, cohort enrichment, and biological interpretation. In this review, we synthesize evidence on AD PRSs across multiple biological and clinical scales, moving from genes and molecular pathways to biomarkers, brain structure and function, cognition, behavior, and clinical translation. Genome-wide PRSs capture aggregate inherited risk, whereas pathway-, tissue-, cell-type-, and biomarker-specific PRSs may help clarify the biological routes through which genetic susceptibility is expressed, including amyloid and tau metabolism, lipid homeostasis, endosomal trafficking, immune regulation, glial activation, proteostasis, and mitochondrial quality control. Evidence indicates that AD PRSs are most consistently associated with amyloid-related biomarkers, while associations with tau, neurodegeneration, brain atrophy, functional connectivity, cognitive decline, and neuropsychiatric manifestations are more heterogeneous and often depend on APOE, disease stage, biomarker context, and variable computation methodologies. Although PRSs show promise for research enrichment and mechanistic stratification, their individual-level clinical utility remains limited by modest predictive performance, ancestry-related transferability, calibration challenges, and ethical considerations. Future progress will require multi-ancestry cohorts, integration of common and rare variation, multi-omic annotation, longitudinal modeling, and multimodal prediction frameworks. Ultimately, PRSs are best viewed not as stand-alone diagnostic tools, but as cross-scale instruments for linking inherited susceptibility to the heterogeneous biological and clinical manifestations of AD.