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Volume 27
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10.3390/ijms27021004
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Review

Apolipoprotein E4 in Alzheimer’s Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment

by
Nour F. Al-Ghraiybah
1,2,
Amer E. Alkhalifa
1,2,
Yutaka Itokazu
1,
Taylor O. Farr
1,
Naima C. Perez
1,
Hande Ali
3 and
Amal Kaddoumi
1,*
1
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
2
Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
3
Faculty of Pharmacy, Zonguldak Bülent Ecevit University, Zonguldak 67100, Türkiye
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(2), 1004; https://doi.org/10.3390/ijms27021004 (registering DOI)
Submission received: 16 December 2025 / Revised: 12 January 2026 / Accepted: 16 January 2026 / Published: 19 January 2026
(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)
Versions Notes

Abstract

Alzheimer’s 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–brain 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’s effects on AD pathology and BBB function. We then discuss ApoE’s 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—whether they involve anti-amyloid therapy or other pharmacological agents used for AD—emphasizing the importance of personalized medicine approaches for patients with this high-risk allele. This review aims to provide an updated overview of ApoE4’s 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.
Keywords: Alzheimer’s disease; Apolipoprotein E; ApoE4; amyloid-β; blood–brain barrier; lipid metabolism; cholesterol; monoclonal antibodies; precision medicine Alzheimer’s disease; Apolipoprotein E; ApoE4; amyloid-β; blood–brain barrier; lipid metabolism; cholesterol; monoclonal antibodies; precision medicine

Share and Cite

MDPI and ACS Style

Al-Ghraiybah, N.F.; Alkhalifa, A.E.; Itokazu, Y.; Farr, T.O.; Perez, N.C.; Ali, H.; Kaddoumi, A. Apolipoprotein E4 in Alzheimer’s Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment. Int. J. Mol. Sci. 2026, 27, 1004. https://doi.org/10.3390/ijms27021004

AMA Style

Al-Ghraiybah NF, Alkhalifa AE, Itokazu Y, Farr TO, Perez NC, Ali H, Kaddoumi A. Apolipoprotein E4 in Alzheimer’s Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment. International Journal of Molecular Sciences. 2026; 27(2):1004. https://doi.org/10.3390/ijms27021004

Chicago/Turabian Style

Al-Ghraiybah, Nour F., Amer E. Alkhalifa, Yutaka Itokazu, Taylor O. Farr, Naima C. Perez, Hande Ali, and Amal Kaddoumi. 2026. "Apolipoprotein E4 in Alzheimer’s Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment" International Journal of Molecular Sciences 27, no. 2: 1004. https://doi.org/10.3390/ijms27021004

APA Style

Al-Ghraiybah, N. F., Alkhalifa, A. E., Itokazu, Y., Farr, T. O., Perez, N. C., Ali, H., & Kaddoumi, A. (2026). Apolipoprotein E4 in Alzheimer’s Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment. International Journal of Molecular Sciences, 27(2), 1004. https://doi.org/10.3390/ijms27021004

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