Impact of age and apolipoprotein e ϵ4 status on regional white matter hyperintensity volume and cognition in healthy aging

Objective: White matter hyperintensity (WMH) volume is a neuroimaging marker of lesion load related to small vessel disease that has been associated with cognitive aging and Alzheimer's disease (AD) risk. Method: The present study sought to examine whether regional WMH volume mediates the relationship between APOE ϵ4 status, a strong genetic risk factor for AD, and cognition and if this association is moderated by age group differences within a sample of 187 healthy older adults (APOE ϵ4 status [carrier/non-carrier] = 56/131). Results: After we controlled for sex, education, and vascular risk factors, ANCOVA analyses revealed significant age group by APOE ϵ4 status interactions for right parietal and left temporal WMH volumes. Within the young-old group (50-69 years), ϵ4 carriers had greater right parietal and left temporal WMH volumes than non-carriers. However, in the old-old group (70-89 years), right parietal and left temporal WMH volumes were comparable across APOE ϵ4 groups. Further, within ϵ4 non-carriers, old-old adults had greater right parietal and left temporal WMH volumes than young-old adults, but there were no significant differences across age groups in ϵ4 carriers. Follow-up moderated mediation analyses revealed that, in the young-old, but not the old-old group, there were significant indirect effects of ϵ4 status on memory and executive functions through left temporal WMH volume. Conclusions: These findings suggest that, among healthy young-old adults, increased left temporal WMH volume, in the context of the ϵ4 allele, may represent an early marker of cognitive aging with the potential to lead to greater risk for AD.