Apolipoprotein E (APOE) in Alzheimer’s Disease: Mechanisms, Modifiers, and Therapeutic Implications

Apolipoprotein E (APOE) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). The three major isoforms APOE2, APOE3, and APOE4 differ structurally and functionally, resulting in marked differences in disease susceptibility and progression. APOE regulates key processes including lipid metabolism, amyloid-β (Aβ) aggregation and clearance, tau pathology, neuroinflammation, and blood–brain barrier integrity. APOE4 is associated with impaired Aβ clearance, increased aggregation, chronic neuroinflammation, synaptic dysfunction, and vascular instability, collectively accelerating neurodegeneration, whereas APOE2 confers relative protection. This review provides a concise synthesis of APOE biology, isoform-specific mechanisms, and major disease pathways. It further highlights key modifiers such as sex, ancestry, and lifestyle factors, and summarizes emerging therapeutic strategies targeting APOE pathways. Finally, current research gaps and future directions toward precision medicine are discussed.