UC San Diego

While the apolipoprotein E (APOE) ε4 allele promotes blood–brain barrier (BBB) permeability and microstructural disruption, its specific contribution to white matter hyperintensity (WMH) pathological heterogeneity remains unknown. We measured BBB permeability (Ktrans) in 31 and microstructure in 59 cognitively normal older adults with WMHs and normal‐appearing white matter (NAWM) using dynamic contrast‐enhanced magnetic resonance imaging and restriction spectrum imaging (RSI). Linear mixed‐effects models (LMMs) examined differences between WMHs and NAWM by APOE ε4 status. In APOE ε4 carriers, Ktrans was elevated and restricted isotropic diffusion (RI) was reduced within WMHs compared to NAWM. This effect was absent in non‐carriers. In contrast, reduced restricted directional diffusion and elevated isotropic free water within WMHs was observed in both genotypes. Ktrans did not correlate with brain microstructure. Our data suggest that WMHs comprise both APOE ε4‐related and APOE ε4‐independent pathological components. These findings implicate neurovascular and non‐vascular mechanisms through which APOE ε4 may contribute to WMH pathological heterogeneity. Apolipoprotein E (APOE) white matter hyperintensities (WMHs) show higher blood–brain barrier permeability and lower restricted isotropic diffusion. Additional microstructure abnormalities in WMHs are APOE ε4 independent. Permeability and microstructure are independent features of WMH pathology. APOE ε4 contributes to WMH burden through a distinct vascular phenotype.