APOE ε4-related blood-brain barrier disruption and APOE ε4-independent microstructural abnormalities in white matter hyperintensities.

INTRODUCTION: 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. METHODS: We measured BBB permeability (K trans) 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. RESULTS: In APOE ε4 carriers, K trans 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. K trans did not correlate with brain microstructure. DISCUSSION: 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.