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

Background: Carrying the Apolipoprotein (APOE) 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. Objective: This study tested the interactive effect of APOE status and multiple vascular comorbidities on white matter (WM) microstructure in aging and early AD. Methods: 195 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. Results: There was a main effect of APOE, with APOE 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 APOE genotype and vascular burden was also found for all diffusion indices. Post-hoc 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. Conclusions: These findings indicate an interactive effect of a risk gene and vascular comorbidities on WM integrity in aging and early AD.