Effects of APOE on brain white matter microstructure in healthy adults

Objectives: APOE is related to cholesterol transport and clearance and brain white matter (WM) properties involving myelin, of which cholesterol is a major component. Diffusion tensor imaging enables in vivo investigations of brain WM, and could increase our understanding of the pathways leading to Alzheimer disease. The main objective was to investigate the association between APOE and diffusion tensor imaging-derived indices of WM microstructure. Methods: Healthy participants were assessed on a range of neuropsychological measures, genotyped, and underwent MRI. A total of 203 volunteers (aged 21.1-69.9 years, mean = 47.6, SD = 14.9) with APOE genotypes epsilon 2/epsilon 3 (n = 30), epsilon 3/epsilon 3 (n = 113), and epsilon 3/epsilon 4 (n = 60) were included. Results: There were widespread increases in mean and radial diffusion in carriers of the epsilon 3/epsilon 4 alleles compared with epsilon 3/epsilon 3 with medium to strong effect sizes (Cohen's d = 0.77-0.79). No interactions between genotype and age were observed, indicating relatively stable differences from early adulthood. The results were independent of presence of dementia in close family. We also observed increased mean and radial diffusion and decreased fractional anisotropy in carriers of the epsilon 2/epsilon 3 alleles compared with epsilon 3/epsilon 3 carriers. No significant differences were found between epsilon 2/epsilon 3 and epsilon 3/epsilon 4. Conclusions: APOE affects microstructural properties of the brain WM from early adulthood, but the specific allelic effects do not directly reflect the associated risk of developing Alzheimer disease. The role of APOE in cholesterol transport, the high density of cholesterol in myelin, and the specific effects on radial diffusivity support a putative functional role of APOE in modulating myelin-related processes in the brain. Neurology (R) 2012;79:1961-1969