{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T21:16:22Z","timestamp":1790111782159,"version":"4.0.1"},"reference-count":290,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T00:00:00Z","timestamp":1738108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>Genetic diversity in the apolipoprotein E (ApoE) gene has been identified as the major susceptibility genetic risk factor for sporadic Alzheimer\u2019s disease (SAD). Specifically, the <jats:italic>ApoE\u03b54<\/jats:italic> allele is a significant risk factor for SAD, while <jats:italic>ApoE\u03b52<\/jats:italic> allele provides protection compared to the more common <jats:italic>ApoE\u03b53<\/jats:italic> allele. This review discusses the role of the ApoE in AD and other neurodegenerative disorders. ApoE, a cholesterol transport protein, influences several pathways involved in neurodegeneration, particularly in AD. Beyond its established role in amyloid <jats:italic>\u03b2<\/jats:italic>-protein (A\u03b2) metabolism and deposition, ApoE also impacts tau pathology, neurodegeneration, and the microglial response to AD. The review aims to provide an updated overview of ApoE\u2019s diverse roles, emphasizing its involvement in A\u03b2 clearance through ApoE receptors. It also covers ApoE\u2019s influence in other neurodegenerative diseases like Parkinson\u2019s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Huntington\u2019s disease (HD), vascular dementia (VD), and multiple sclerosis (MS). New research highlights the interaction between ApoE and presenilin (PS), suggesting connections between familial AD (FAD) and SAD. The review also explores protective effects of ApoE mutations against AD and ApoE4-induced tauopathy, neurodegeneration, and neuroinflammation. The insights from this comprehensive update could indeed lead to new therapeutic strategies for neurodegenerative diseases.<\/jats:p>","DOI":"10.3389\/fnagi.2025.1535280","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T06:47:13Z","timestamp":1738133233000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":41,"title":["Multi-functional role of apolipoprotein E in neurodegenerative diseases"],"prefix":"10.3389","volume":"17","author":[{"given":"Sadequl","family":"Islam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arshad","family":"Noorani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Michikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1194\/jlr.P071639","article-title":"Defective cholesterol metabolism in amyotrophic lateral sclerosis","volume":"58","author":"Abdel-Khalik","year":"2017","journal-title":"J. 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