A Comprehensive Review of Genetic Risk Factors for Alzheimer’s Disease Development

Abstract: Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder with a complex genetic basis involving both rare mutations and common variants. This review provides a comprehensive synthesis of established and emerging genetic risk factors implicated in AD pathogenesis. Mendelian forms are strongly associated with mutations in APP, PSEN1, and PSEN2, whereas the APOE ε4 allele remains the most robust genetic risk factor for late-onset AD. Recent Genome- Wide Association Studies (GWAS) have uncovered additional susceptibility loci, including TREM2, CLU, ABCA7, and SORL1, which reflect diverse biological pathways such as amyloid metabolism, lipid regulation, and immune response. The review also highlights the roles of epigenetic mechanisms such as DNA methylation and histone modifications, as well as geneenvironment interactions in modulating disease risk and progression. Although substantial progress has been made in identifying genetic contributors, translating these findings into clinical applications remains challenging. This article underscores the need for integrative, multi-omic approaches and population-diverse studies to enhance risk prediction and enable personalized interventions for prevention and therapy in AD.