APOE4 genotype, blood-brain barrier leakage and ischaemic stroke subtype and location

Laing, K. K.; Valdes Hernandez, M. d. C.; Thrippleton, M.; Makin, S.; Chappell, F. M.; Dando, O.; Vasoya, D.; Armitage, P. A.; Wardlaw, J. M.

doi:10.64898/2026.06.05.730537

bioRxiv · 10.64898/2026.06.05.730537

APOE4 genotype, blood-brain barrier leakage and ischaemic stroke subtype and location

Laing, K. K.·Valdes Hernandez, M. d. C.·Thrippleton, M.·Makin, S.·Chappell, F. M.·Dando, O.·Vasoya, D.·Armitage, P. A.·Wardlaw, J. M.

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Abstract

BackgroundApolipoprotein E (APOE) has been implicated in blood-brain barrier (BBB) dysfunction and may influence ischaemic cerebrovascular disease and cerebral small-vessel disease (cSVD). This study examined associations between APOE genotype, BBB permeability, and infarct distribution in patients with mild ischemic stroke. MethodsWe recruited patients with mild ischemic stroke who underwent structural and dynamic contrast-enhanced MRI (DCE-MRI) and APOE genotyping. Infarct type and location, white matter hyperintensities (WMH), and perivascular spaces (PVS) were assessed. BBB-related metrics were quantified using fractional plasma volume (vP) and permeability-surface area product (PS) across five brain regions of interest: deep grey matter (DGM), hippocampus, thalamus, normal-appearing white matter (NAWM), and WMH. Associations between genotype, BBB metrics, vascular risk factors, and age were evaluated using linear mixed-effects models. Binary logistic regression was also applied to assess the association between APOE status and infarct location by vascular territory (anterior vs posterior circulation). ResultsAmong 147 patients with APOE genotype and BBB measures, APOE4 carriers (n=44) demonstrated a greater proportion of posterior circulation infarcts than E3/E3 individuals (n=80; 56.4% versus 32.9%), including higher frequencies of posterior cerebral artery cortical, posterior borderzone, and thalamic infarcts. Mean PS and vP did not differ significantly by genotype. Increasing age was associated with lower PS across multiple regions and lower vP in WMH, while higher vascular risk burden was associated with lower vP in NAWM and WMH. Inclusion of regional BBB metrics did not substantially alter APOE4 effect estimates in infarct-location models. ConclusionsAPOE4 carriers showed a posterior-predominant infarct distribution despite similar BBB permeability and vascularity measures. Age and vascular risk burden were more strongly associated with BBB-related imaging metrics than APOE genotype. These findings add to evidence suggesting that APOE genotype may influence regional cerebrovascular vulnerability and that this effect is unlikely to be fully explained by DCE-MRI-derived measures of BBB permeability and vascularity alone.

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Laing, K. K., Valdes Hernandez, M. d. C., Thrippleton, M., Makin, S., Chappell, F. M., Dando, O., Vasoya, D., Armitage, P. A., Wardlaw, J. M.. 2026-06-10. APOE4 genotype, blood-brain barrier leakage and ischaemic stroke subtype and location. https://doi.org/10.64898/2026.06.05.730537

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