APOEε4 Influences White Matter Hyperintensity Across Brain Regions in Cognitively Normal Adults

Purpose White matter hyperintensity (WMH) is associated with heterogeneous pathologies. In neurodegeneration, the prevailing hypothesis is that WMH primarily reflects vascular pathology, exerting an additive effect in AD. Alternatively, a subset of WMH may arise secondary to AD‐related pathophysiology. APOE4 genotype, the greatest genetic risk factor for late‐onset AD, impacts the blood‐brain barrier and WMH burden. Herein, we investigate the association between regional WMH burden and APOE4 allelic dosage in cognitively normal individuals. Methods We used deep learning to automatically segment WMH from T2‐FLAIR MRI from 154 cognitively intact individuals older than 50. We mapped WMH to 4 specific brain regions (lobar, periventricular, basal ganglia and infratentorial, further parcellated into sub‐regions, Table 1) using atlas‐based registration and FastSurfer. WMH volumes were adjusted for total intracranial volume and normalized using log transformation. The APOE4 groups were compared for WMH burden using linear regression, controlling for age and vascular risk factors (hypertension, diabetes, hypercholesterolemia, cigarette smoking). For brain regions where more than 20% of participants had no WMH, a two‐part hurdle model was applied. Results We included 13 APOE4 homozygotes, 50 heterozygotes (ε4/ ε3) and 91 non‐carriers. Compared to non‐carriers, APOEε4 homozygotes exhibited significantly greater WMH burden in the whole brain, periventricular (posterior) and lobar regions (Figure 1a). Homozygotes exhibited a significantly greater WMH burden in the whole brain and posterior periventricular region, when compared to heterozygotes (Figure 1b). No significant whole‐brain or region‐specific differences were observed between heterozygotes and non‐carriers (Figure 1c). Conclusion In cognitively intact individuals at risk for AD, APOE4 homozygosity is associated with significantly greater WMH burden, particularly in the posterior periventricular space, after controlling for age and vascular risk factors. The relationship between regional‐specific WMH burden and neurodegeneration warrants further investigation. image image