Genetic risk of dementia modifies obesity effects on white matter myelin in cognitively healthy adults.

APOE-ε4 is a major genetic risk factor for late-onset Alzheimer's disease that interacts with other risk factors, but the nature of such combined effects remains poorly understood. We quantified the impact of APOE-ε4, family history (FH) of dementia, and obesity on white matter (WM) microstructure in 165 asymptomatic adults (38-71 years old) using quantitative magnetization transfer and neurite orientation dispersion and density imaging. Microstructural properties of the fornix, parahippocampal cingulum, and uncinate fasciculus were compared with those in motor and whole-brain WM regions. Widespread interaction effects between APOE, FH, and waist-hip ratio were found in the myelin-sensitive macromolecular proton fraction from quantitative magnetization transfer. Among individuals with the highest genetic risk (FH+ and APOE-ε4), obesity was associated with reduced macromolecular proton fraction in the right parahippocampal cingulum, whereas no effects were present for those without FH. Risk effects on apparent myelin were moderated by hypertension and inflammation-related markers. These findings suggest that genetic risk modifies the impact of obesity on WM myelin consistent with neuroglia models of aging and late-onset Alzheimer's disease.