Impact of age and apolipoprotein E 4 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 epsilon 4 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 epsilon 4 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 epsilon 4 status interactions for right parietal and left temporal WMH volumes. Within the young-old group (50-69 years), epsilon 4 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 epsilon 4 groups. Further, within epsilon 4 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 epsilon 4 carriers. Follow-up moderated mediation analyses revealed that, in the young-old, but not the old-old group, there were significant indirect effects of epsilon 4 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 epsilon 4 allele, may represent an early marker of cognitive aging with the potential to lead to greater risk for AD.