APOE-driven lipid dysregulation in Alzheimer’s disease: from glia to myelin

Abstract The APOE4 allele is the predominant genetic risk factor for late-onset Alzheimer’s disease (AD), and its pathological influence is increasingly understood through the lens of lipid biology. APOE functions as the primary lipoprotein in the central nervous system, coordinating the distribution of cholesterol, phospholipids, and fatty acids among neurons and glial cells to sustain membrane integrity, synaptic function, and myelin maintenance. The E4 isoform carries structural alterations that compromise its lipid carrying capacity and receptor interactions, with consequences that extend across multiple brain cell types. In this review, we synthesize current evidence on how APOE4 disrupts lipid homeostasis in a cell type specific manner, covering astrocytic lipid buffering and oxidative stress responses, microglial phagocytic and lysosomal dysfunction, oligodendrocyte cholesterol handling and myelin biosynthesis, and neuronal lipid clearance. We also address the relationship between APOE isoforms and the hallmark pathologies of AD, including amyloid beta accumulation and tau propagation. Insights from protective natural variants such as APOE2, Christchurch, and Jacksonville are discussed in the context of therapeutic target identification. Evidence drawn from human postmortem studies, neuroimaging, single-cell transcriptomics, and iPSC derived brain cell models converges on a model suggests that disrupted glial lipid metabolism may contribute early in disease, although whether it initiates or amplifies pathology remains unresolved. Targeting APOE-mediated lipid pathways therefore offers a promising and mechanistically grounded avenue for disease modifying intervention in AD.