Interactive effects of <i>APOE</i> ɛ4 status and vascular burden on white matter microstructural integrity in aging with and without neurocognitive decline

BackgroundCarrying the Apolipoprotein (<i>APOE</i>) ε4 allele lowers age of onset and increases Alzheimer's disease (AD) risk. Neuropathological findings suggest a mixed etiology in many AD patients, and vascular pathology is common.ObjectiveThis study tested the interactive effect of <i>APOE</i> status and multiple vascular comorbidities on white matter (WM) microstructure in aging and early AD.Methods195 participants from the VPH-DARE@IT dataset were stratified in low/high vascular burden based on the Framingham Risk Score (BMI version). Tract-based spatial statistics was used for WM analyses.ResultsThere was a main effect of <i>APOE</i>, with <i>APOE</i> ɛ4 carriers having higher fractional anisotropy (FA) and lower axial diffusivity (AxD), mean diffusivity (MD), and radial diffusivity (RD) than non-carriers. There was a main effect of vascular burden with lower FA and higher AxD, MD, and RD in the high-burden than the low-burden group. A significant interaction between <i>APOE</i> genotype and vascular burden was also found for all diffusion indices. <i>Post-hoc</i> comparisons revealed lower left hemisphere WM integrity when comparing the low risk group (i.e., non-carriers low burden) to intermediate risk groups (i.e., non-carriers high burden or ɛ4 carriers low burden). The contrasts between the two intermediate risk groups showed altered WM integrity bilaterally. Only the non-carriers high burden showed greater alterations in WM integrity when compared with the high risk group (i.e., ɛ4 carriers high burden) mainly in right hemisphere tracts.ConclusionsThese findings indicate an interactive effect of a risk gene and vascular comorbidities on WM integrity in aging and early AD.