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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2025-06-01
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| author | Aiwei Liu Tingxu Wang Liu Yang Yu Zhou |
| author_facet | Aiwei Liu Tingxu Wang Liu Yang Yu Zhou |
| author_sort | Aiwei Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e370e9fa5a8946d89d3cc3a0ade56c87 |
| institution | Kabale University |
| issn | 2076-3425 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Brain Sciences |
| spelling | doaj-art-e370e9fa5a8946d89d3cc3a0ade56c872025-08-20T03:58:30ZengMDPI AGBrain Sciences2076-34252025-06-0115767510.3390/brainsci15070675The APOE–Microglia Axis in Alzheimer’s Disease: Functional Divergence and Therapeutic Perspectives—A Narrative ReviewAiwei Liu0Tingxu Wang1Liu Yang2Yu Zhou3School of Basic Medical Sciences, Qingdao University, Qingdao 266071, ChinaSchool of Basic Medical Sciences, Qingdao University, Qingdao 266071, ChinaDepartment of Physiology, Binzhou Medical University, Yantai 264003, ChinaSchool of Life Sciences and Health, University of Health and Rehabilitation Sciences, Qingdao 266000, ChinaApolipoprotein 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.https://www.mdpi.com/2076-3425/15/7/675Alzheimer’s diseaseapolipoprotein Emicrogliainflammationphagocytosislipid metabolism |
| spellingShingle | Aiwei Liu Tingxu Wang Liu Yang Yu Zhou The APOE–Microglia Axis in Alzheimer’s Disease: Functional Divergence and Therapeutic Perspectives—A Narrative Review Brain Sciences Alzheimer’s disease apolipoprotein E microglia inflammation phagocytosis lipid metabolism |
| title | The APOE–Microglia Axis in Alzheimer’s Disease: Functional Divergence and Therapeutic Perspectives—A Narrative Review |
| title_full | The APOE–Microglia Axis in Alzheimer’s Disease: Functional Divergence and Therapeutic Perspectives—A Narrative Review |
| title_fullStr | The APOE–Microglia Axis in Alzheimer’s Disease: Functional Divergence and Therapeutic Perspectives—A Narrative Review |
| title_full_unstemmed | The APOE–Microglia Axis in Alzheimer’s Disease: Functional Divergence and Therapeutic Perspectives—A Narrative Review |
| title_short | The APOE–Microglia Axis in Alzheimer’s Disease: Functional Divergence and Therapeutic Perspectives—A Narrative Review |
| title_sort | apoe microglia axis in alzheimer s disease functional divergence and therapeutic perspectives a narrative review |
| topic | Alzheimer’s disease apolipoprotein E microglia inflammation phagocytosis lipid metabolism |
| url | https://www.mdpi.com/2076-3425/15/7/675 |
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