Impact of Apolipoprotein E4 on blood-brain barrier integrity in target replacement murine models: a systematic review and meta-analysis.
Level 5 - mechanism / opinion, no new human data
Systematic review and meta-analysis of preclinical animal (murine) studies
PubMed 42098772 · doi:10.1186/s13195-026-02018-3
What was done
A systematic search of MEDLINE, Embase, Scopus, and Web of Science (March-April 2025) identified preclinical studies evaluating blood-brain barrier integrity, vascular morphology, and cerebral blood flow in transgenic APOE-targeted replacement or knock-in mice. Reporting quality and risk of bias were assessed using CAMARADES and SYRCLE tools. Random-effects meta-analyses were conducted where data permitted, supplemented by narrative synthesis.
What was found
Eighteen studies met inclusion criteria, with 7 contributing to meta-analysis. APOE4 mice showed a significant reduction in cerebral blood flow compared to controls (SMD = -2.87, 95% CI: -5.14 to -0.604, df = 2.66) and a non-significant negative trend in vascular morphology expression. Narrative synthesis identified three key mechanistic pathways: insulin resistance and PI3K/AKT-mTOR signalling, Cyclophilin A-NFκB-MMP9 activation, and occludin/extracellular matrix remodelling.
Why it matters
This review synthesises preclinical evidence demonstrating that the APOE4 allele drives early cerebrovascular dysfunction and blood-brain barrier impairment, clarifying potential vascular mechanisms in Alzheimer's disease pathogenesis.
Limits
Findings are limited to animal models and cannot establish clinical effects in humans. Primary studies showed frequent shortcomings in randomisation, blinding, and sample size justification, alongside substantial heterogeneity in mouse age, sex, and outcome measurement techniques. Only 7 of 18 included studies provided sufficient data for meta-analysis.
Cited by
- supports Humanized APOE4 mice exhibit reduced cerebral blood flow, increased blood-brain barrier leakage, and cognitive deficits in novel object recognition and location tasks compared to APOE3 mice.