Mechanistic role of APOE lipidation in Alzheimer's disease pathogenesis

The apolipoprotein E (APOE) ε4 allele is the primary genetic driver of late-onset Alzheimer's disease (AD), a complex neurodegenerative disorder characterized by the interplay of amyloid-β (Aβ) accumulation, tau pathology, neuroinflammation, and lipid metabolism dysfunction. Emerging evidence suggests that these pathological hallmarks are fundamentally linked to deficits in neuroplasticity and the continuous turnover of synapses. A growing body of evidence highlights APOE lipidation, a process by which APOE is loaded with lipids via cellular transporters such as ABCA1, as a key determinant of APOE function and toxicity. While lipidated APOE2 and APOE3 facilitate cholesterol transport and Aβ clearance, lipid-poor APOE4 is associated with impaired receptor-mediated clearance of Aβ, disrupted microglial function, increased neuroinflammation, and synaptic deficits. Furthermore, APOE lipidation status differentially influences tau pathology, potentially linking cholesterol dysregulation to tau hyperphosphorylation and aggregation. Here, we systematically examine the mechanistic role of APOE lipidation in AD pathogenesis, focusing on its effects on Aβ and tau pathology. We also discuss how dysregulation of APOE lipidation may serve as a central molecular mechanism connecting APOE4 to multiple pathological hallmarks of AD. This review examines how APOE lipidation is involved in amyloid-related and tau pathology in AD.