{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:06:55Z","timestamp":1792789615064,"version":"4.5.0"},"reference-count":135,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Among the genetic risk factors linked to AD, the Apolipoprotein E4 (ApoE4) remains the strongest. It is well known that carrying the ApoE4 isoform is associated with advanced AD pathology, blood\u2013brain barrier (BBB) disruption, and changes in lipid metabolism. In this review, we provide an overview of the role of centrally and peripherally produced ApoE in AD. After this introduction, we focus on new findings regarding ApoE4\u2019s effects on AD pathology and BBB function. We then discuss ApoE\u2019s role in lipid metabolism in AD, highlighting examples of lipid changes caused by carrying the ApoE4 isoform. Next, the review explores the implications of ApoE4 isoforms for current treatments\u2014whether they involve anti-amyloid therapy or other pharmacological agents used for AD\u2014emphasizing the importance of personalized medicine approaches for patients with this high-risk allele. This review aims to provide an updated overview of ApoE4\u2019s effects on AD pathology and treatment. By integrating recent discoveries, it underscores the critical need to consider ApoE4 status in both research and clinical settings to enhance therapeutic strategies and outcomes for individuals with AD.<\/jats:p>","DOI":"10.3390\/ijms27021004","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T08:36:33Z","timestamp":1768898193000},"page":"1004","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Apolipoprotein E4 in Alzheimer\u2019s Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7278-9134","authenticated-orcid":false,"given":"Nour F.","family":"Al-Ghraiybah","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6872-4780","authenticated-orcid":false,"given":"Amer E.","family":"Alkhalifa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7800-8262","authenticated-orcid":false,"given":"Yutaka","family":"Itokazu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor O.","family":"Farr","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naima C.","family":"Perez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hande","family":"Ali","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Zonguldak B\u00fclent Ecevit University, Zonguldak 67100, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9792-7766","authenticated-orcid":false,"given":"Amal","family":"Kaddoumi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/S1474-4422(20)30412-9","article-title":"APOE and Alzheimer\u2019s disease: Advances in genetics, pathophysiology, and therapeutic approaches","volume":"20","author":"Das","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s13024-022-00574-4","article-title":"ApoE in Alzheimer\u2019s disease: Pathophysiology and therapeutic strategies","volume":"17","author":"Raulin","year":"2022","journal-title":"Mol. 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