# The APOE paradox: divergent genetic influences on hemorrhagic stroke risk—A meta-analysis

## TL;DR

This study clarifies how different APOE gene variants affect the risk of hemorrhagic stroke through a meta-analysis of 24 studies.

## Contribution

The study provides a systematic evaluation of APOE's role in hemorrhagic stroke risk using a meta-analysis approach.

## Key findings

- APOE ε2/ε2, ε2/ε4, ε2, and ε4/ε4 genotypes are significantly associated with increased hemorrhagic stroke risk.
- The ε4 allele also shows a significant increase in hemorrhagic stroke risk.
- The meta-analysis included 24 studies with over 8,000 stroke patients and 26,000 controls.

## Abstract

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.

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 ε3/ε3 genotype served as the reference genotype in all studies, and only those studies with ε3/ε3 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 (StataCorp LLC, College Station, Texas, United States).

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.

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.