SYSTEMATIC REVIEW article
Front. Stroke
Sec. Genetics and Omics of Stroke
The APOE Paradox: Divergent Genetic Influences on Hemorrhagic Stroke Risk – A Meta-Analysis
Provisionally accepted
- 1All India Institute of Medical Sciences, New Delhi, India
- 2Yale School of Medicine Department of Neuroscience, New Haven, United States
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(1) Background: Apolipoprotein E (APOE) regulates lipid metabolism and neuronal repair, yet its alleles show contrasting effects on hemorrhagic stroke (HS) risk. While some variants increase susceptibility, others appear protective, leading to inconsistent findings. This meta-analysis systematically evaluates the APOE-HS association to clarify its role in stroke pathophysiology. (2) Methods: A comprehensive literature search was conducted across multiple databases up to January 31, 2025, using the keywords: ('Apolipoprotein E' OR 'APOE' OR 'APOE genotype') AND ('Single Nucleotide Polymorphisms' OR 'SNP') AND ('Hemorrhagic stroke' OR 'HS' OR 'Intracerebral Hemorrhage' OR 'ICH'). The APOE e3/e3 genotype served as the reference genotype in all studies, and only those studies with e3/e3 genotype were included in the analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and statistical analyses were performed using STATA version 13.0. (3) Results: A total of 24 studies comprising 8,269 HS patients and 26,321 controls were included. Meta-analysis revealed a significant association of APOE ε2/ε2 [OR = 1.93, 95% CI = 1.32–2.81], ε4/ε4 [OR = 1.60, 95% CI = 1.21–2.13], ε2/ε4 [OR = 1.81, 95% CI = 1.34–2.44], ε2 [OR = 1.23, 95% CI = 1.12–1.35], and ε4 [OR = 1.31, 95% CI = 1.14–1.51] with an increased risk of HS. (4) Conclusion: Our findings suggest that APOE ε2/ε2, ε2/ε4, ε2, and ε4/ε4 genotypes and the ε4 allele are associated with an elevated risk of HS. These results highlight the potential role of APOE genotypes in HS susceptibility and warrant further investigation.
Keywords: APOE alleles, APOE genotype, Apolipoprotein E, hemorrhagic stroke, intracerebral hemorrhage
Received: 12 Aug 2025; Accepted: 30 Jan 2026.
Copyright: © 2026 Nath, Rai, Misra and Kumar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Pradeep Kumar
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