APOE4-driven lipid metabolic dysregulation in Alzheimer's disease: Multi-pathway mechanisms and therapeutic perspectives.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by senile plaques deposition and hyperphosphorylated Tau. As the primary genetic risk factor for late-onset AD (LOAD), Apolipoprotein E4 (APOE4) might drive the core pathological progression of this disease through lipid metabolism dysregulation. Due to its relatively lower lipid-binding efficiency compared to APOE3, APOE4 impairs cholesterol efflux, leading to lipid droplet (LD) accumulation and lysosomal dysfunction in neurons and glial cells. APOE4 also disrupts the microglia TREM2-APOE signaling axis asnd exacerbates neuroinflammation by activating the TLR4/NF-κB pathway. In oligodendrocytes, APOE4 induces dysregulation of the LXRβ/ABCA1 pathway and results in sphingolipid metabolism imbalance and demyelination. Furthermore, APOE4 compromises the integrity of blood-brain barrier and activates the CypA-MMP9 pathway, facilitating the infiltration of peripheral inflammatory cytokine and cerebrovascular pathology. This article summarized the evidence that APOE4 affects lipid metabolism through various pathways and proposed the potential therapeutic strategies to alleviate the progression of AD.