{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:11:54Z","timestamp":1793052714938,"version":"4.5.0"},"reference-count":155,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["32371211"],"award-info":[{"award-number":["32371211"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Apolipoprotein E (APOE) alleles play distinct roles in the pathogenesis of Alzheimer\u2019s disease (AD), with APOE\u03b54 being the strongest genetic risk factor for late-onset AD, while APOE\u03b52 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 APOE\u03b54-mediated disruption of microglial homeostasis via pathways such as TREM2 signaling, NF-\u03baB\/NLRP3 activation, ACSL1 upregulation, and HIF-1\u03b1 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\u2013microglia axis.<\/jats:p>","DOI":"10.3390\/brainsci15070675","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T08:50:57Z","timestamp":1750755057000},"page":"675","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The APOE\u2013Microglia Axis in Alzheimer\u2019s Disease: Functional Divergence and Therapeutic Perspectives\u2014A Narrative Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6375-3323","authenticated-orcid":false,"given":"Aiwei","family":"Liu","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingxu","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Binzhou Medical University, Yantai 264003, China"},{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Qingdao University, Qingdao 266071, China"},{"name":"Institute of Brain Sciences and Related Disorders, Qingdao University, Qingdao 266071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8193-7561","authenticated-orcid":false,"given":"Yu","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Life Sciences and Health, University of Health and Rehabilitation Sciences, Qingdao 266000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Weissbrod, P.A., and Francis, D.O. 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