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

Abstract

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.

Keywords: Alzheimer’s disease; apolipoprotein E; inflammation; lipid metabolism; microglia; phagocytosis.

Figure 1

Molecular mechanisms by which APOE4 modulates the DAM/MGnD phenotype in microglia. In neurodegenerative conditions, phosphatidylserine exposed by apoptotic neurons activates the TREM2 receptor on microglia, initiating downstream signaling cascades through its interaction with DAP12. This triggers two key pathways: (1) SYK kinase phosphorylation directly upregulates DAM/MGnD-related genes and (2) collaboration with the APOE signaling pathway promotes DAM/MGnD phenotype acquisition. However, APOE4 disrupts this process via multiple mechanisms: (1) upregulating miR-155 to suppress IFNγ signaling, thereby impairing DAM activation; (2) increasing the expression of the transcription factor Spi-1 (PU.1), which activates the ITGB8-TGF-β pathway to antagonize the pro-DAM effects of TREM2-APOE. Notably, APOEε4 neutrophils exacerbate this suppression by releasing IL-17F, which engages microglial IL-17RA receptors. Separately, the APOE-VCAM1 interaction has been shown to promote DAM/MGnD phenotype formation.

Figure 2

Inflammatory signaling pathways involved in microglial regulation by APOEε4. In microglia, LPS binding to TLR4 activates NF-κB and p38 MAPK signaling pathways, driving pro-inflammatory cytokine release (TNF-α, IL-1β, IL-6) and NLRP3 inflammasome-dependent IL-1β secretion—processes significantly exacerbated by APOEε4. Additionally, APOE4 disrupts mitochondrial autophagy, leading to ROS accumulation, which amplifies inflammatory signaling through NF-κB positive feedback, while mitochondrial damage releases DAMPs that further activate inflammasomes. Furthermore, the APOE4 proteolytic fragment nAPOE41–151 directly binds the TNF-α-promoter to enhance its expression, and APOE4-LilrB3 interaction promotes microglial activation and pro-inflammatory polarization. Notably, APOEε4 also enhances HIF-1α activity, inducing glycolytic reprogramming that sustains microglial inflammatory responses.

Figure 3

APOEε4 disrupts microglial Aβ clearance through multiple convergent mechanisms. APOEε4 promotes the formation of MHC-II microglia, which exhibit enhanced inflammatory responses and Aβ phagocytosis—the former promotes, while the latter suppresses, Aβ plaque accumulation. Additionally, APOEε4 inhibits the TREM2-APOE axis, impairing the formation of MGnD and ARM, both of which enhance Aβ clearance. APOEε4 also disrupts microglial lysosomal function, leading to intracellular Aβ accumulation and promoting plaque formation. Furthermore, APOEε4 downregulates P2RY12, impairing microglial chemotaxis and the ability of microglia to form protective barriers around plaques.

Figure 4

APOEε4 disrupts microglial lipid metabolism, linking it to inflammation and phagocytic deficits. APOEε4 disrupts microglial lipid metabolism by increasing ACSL1-mediated triglyceride synthesis while simultaneously promoting cholesterol uptake and biosynthesis but suppressing cholesterol degradation and efflux, ultimately leading to intracellular cholesterol accumulation and lipid droplets (LDs) formation. The resulting lipid-laden microglia exhibit elevated ROS production, which induces neuronal lipid release, thereby further exacerbating microglial LDs accumulation, establishing a vicious cycle. Moreover, LDs accumulation promotes NF-κB pathway activation with consequent pro-inflammatory cytokine release, whereas cholesterol accumulation impairs lysosomal function and compromises Aβ clearance. These pathological changes collectively drive sustained neuroinflammation, Aβ plaque deposition, and, ultimately, neuronal degeneration and death.