The APOE–Microglia Axis in Alzheimer’s Disease: Functional Divergence and Therapeutic Perspectives—A Narrative Review
Apolipoprotein E (APOE) alleles play distinct roles in the pathogenesis of Alzheimer’s disease (AD), with <i>APOE</i>ε4 being the strongest genetic risk factor for late-onset AD, while <i>APOE</i>ε2 appears protective. Despite extensive research, the precise mechanisms by whi...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
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| Series: | Brain Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3425/15/7/675 |
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| Summary: | Apolipoprotein E (APOE) alleles play distinct roles in the pathogenesis of Alzheimer’s disease (AD), with <i>APOE</i>ε4 being the strongest genetic risk factor for late-onset AD, while <i>APOE</i>ε2 appears protective. Despite extensive research, the precise mechanisms by which <i>APOE</i> alleles contribute to AD pathology remain incompletely understood. Recent advances in multi-omics technologies and single-cell analyses have revealed that <i>APOE</i> 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 <i>APOE</i> alleles differentially regulate microglial activation, inflammatory signaling, phagocytic activity, and lipid metabolism in the context of AD, with a particular focus on the <i>APOE</i>ε4-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 <i>APOE</i> allele-specific contributions to AD pathology, but also highlight novel therapeutic strategies targeting the APOE–microglia axis. |
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| ISSN: | 2076-3425 |