The APOE-Microglia Axis in Alzheimer's Disease: Functional Divergence and Therapeutic Perspectives-A Narrative Review.

Brain sciences 2025

Apolipoprotein E (APOE) alleles play distinct roles in the pathogenesis of Alzheimer's disease (AD), with APOEε4 being the strongest genetic risk factor for late-onset AD, while APOEε2 appears protective. Despite extensive research, the precise mechanisms by which APOE alleles contribute to AD pathology remain incompletely understood. Recent advances in multi-omics technologies and single-cell analyses have revealed that APOE alleles shape microglial phenotypes, thereby affecting amyloid clearance, inflammatory responses, tau pathology, and lipid metabolism. In this review, we provide a detailed overview of how APOE alleles differentially regulate microglial activation, inflammatory signaling, phagocytic activity, and lipid metabolism in the context of AD, with a particular focus on the APOEε4-mediated disruption of microglial homeostasis via pathways such as TREM2 signaling, NF-κB/NLRP3 activation, ACSL1 upregulation, and HIF-1α induction. These insights not only advance our understanding of APOE allele-specific contributions to AD pathology, but also highlight novel therapeutic strategies targeting the APOE-microglia axis.

4 Figures Extracted

Figure 1 PMC

Molecular mechanisms by which APOE4 modulates the DAM/MGnD phenotype in microglia. In neurodegenerative conditions, phosphatidylserine exposed by apop...

Figure 2 PMC

Inflammatory signaling pathways involved in microglial regulation by APOE ε4. In microglia, LPS binding to TLR4 activates NF-κB and p38 MAPK signalin...

Figure 3 PMC

APOE ε4 disrupts microglial Aβ clearance through multiple convergent mechanisms. APOEε4 promotes the formation of MHC-II microglia, which exhibit enha...

Figure 4 PMC

APOE ε4 disrupts microglial lipid metabolism, linking it to inflammation and phagocytic deficits. APOE ε4 disrupts microglial lipid metabolism by inc...