While total white matter hyperintensity (WMH) volume on magnetic resonance imaging (MRI) has been associated with hippocampal atrophy, less is known about how the regional distribution of WMH volume may differentially affect the hippocampus in healthy aging. Additionally, apolipoprotein E (APOE) ε4 carriers may be at an increased risk for greater WMH volumes and hippocampal atrophy in aging. The present study sought to investigate whether regional WMH volume mediates the relationship between age and hippocampal volume and if this association is moderated by APOE ε4 status in a group of 190 cognitively healthy adults (APOE ε4 status [carrier/non-carrier] = 59/131), ages 50-89. Analyses revealed that temporal lobe WMH volume significantly mediated the relationship between age and average bilateral hippocampal volume, and this effect was moderated by APOE ε4 status (-0.020 (SE = 0.009), 95% CI, [-0.039, -0.003]). APOE ε4 carriers, but not non-carriers, showed negative indirect effects of age on hippocampal volume through temporal lobe WMH volume (APOE ε4 carriers: -0.016 (SE = 0.007), 95% CI, [-0.030, -0.003]; APOE ε4 non-carriers: .005 (SE = 0.006), 95% CI, [-0.006, 0.017]). These findings remained significant after additionally adjusting for sex, years of education, hypertension status and duration, cholesterol status, diabetes status, Body Mass Index, history of smoking, and the Wechsler Adult Intelligence Scale-IV Full Scale IQ. There were no significant moderated mediation effects for frontal, parietal, and occipital lobe WMH volumes, with or without covariates. Our findings indicate that in cognitively healthy older adults, elevated WMH volume regionally localized to the temporal lobes in APOE ε4 carriers is associated with reduced hippocampal volume, suggesting greater vulnerability to brain aging and the risk for Alzheimer's disease.
Keywords: APOE ε4; brain aging; hippocampal volume; preclinical Alzheimer's disease risk; regional white matter hyperintensities.
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