Decoding the Genetic Basis of Alzheimer's Disease: A Comprehensive Review of Key Causal and Risk Genes, Pathological Mechanisms, Convergent Pathways, and Emerging Therapeutic Targets
Alzheimer's disease (AD) is the leading cause of dementia worldwide, accounting for approximately 60–70% of all dementia cases. It is a progressive neurodegenerative disorder that results in memory loss, cognitive decline and functional impairment, and affects over 55 million individuals worldwide. The number of affected individuals is projected to reach 139 million by 2050, posing a substantial public health and socioeconomic burden. Pathologically, AD is defined by extracellular deposits of amyloid-β (Aβ) plaques and intracellular accumulation of hyperphosphorylated tau in the form of neurofibrillary tangles (NFTs). There is growing evidence that the pathogenesis of AD is multifactorial, involving genetic, molecular, and environmental factors. This review aims to give a comprehensive overview of the major genes and molecular pathways involved in the pathogenesis of AD, as well as recent advances in genome-wide association studies (GWAS) and emerging therapeutic strategies. The mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) are associated with early-onset familial AD, while late-onset AD is linked to several susceptibility genes identified by GWAS. The molecular mechanisms underlying AD pathogenesis and progression are discussed with respect to major AD-associated genes, such as microtubule-associated protein tau (MAPT), apolipoprotein E (APOE), triggering receptor expressed on myeloid cells 2 (TREM2), sortilin-related receptor 1 (SORL1), bridging integrator 1 (BIN1), phosphatidylinositol-binding clathrin assembly protein (PICALM), Clusterin (CLU), ATP-binding cassette subfamily A member 7 (ABCA7), complement receptor 1 (CR1), acetylcholinesterase (AChE), nuclear factor erythroid 2-related factor 2 (NRF2), and tumor necrosis factor (TNF). Current therapeutic strategies, including anti-amyloid immunotherapy, AChE inhibitors, tau-directed therapies, and emerging gene-targeted approaches, are also discussed. In addition, progress in multi-omics technologies, disease models using induced pluripotent stem cells (iPSC), gene editing with CRISPR-Cas9, and artificial intelligence (AI) analysis are likely to speed up the implementation of precision medicine for early diagnosis, risk prediction, and treatment of Alzheimer's disease.