Longitudinal White Matter Changes in Cognitively Healthy Individuals at Different Genetic Risk for Alzheimer’s Disease

Abstract

Apolipoprotein E ε4 is the most significant genetic risk factor of sporadic Alzheimer's disease. The ε4 allele has been linked to several pathological features of Alzheimer's disease, including white matter degeneration. This project investigated longitudinal white matter changes in cognitively healthy older individuals with different apolipoprotein E gene status. The study population consisted of 41 cognitively healthy 60–76-year-old individuals divided into three groups based on their apolipoprotein E gene status: homozygous (n=13) and heterozygous (n=13) ε4 carriers and non-carriers (n=15). Diffusion tensor imaging scans approximately 2 years apart were used to assess longitudinal white matter microstructure, using fractional anisotropy and mean diffusivity as the metrics of change in white matter microstructure. Tract-based Spatial Statistics was used for exploratory whole-brain analysis within- and between-group. Heterozygous carriers showed greater decrease in fractional anisotropy than non-carriers. However, this result was not significant after adding covariates. In the within-group analysis without covariates, a widespread decrease in fractional anisotropy was observed in all groups. However, the significance disappeared after adding covariates. Similarly, all groups showed widespread longitudinal increase in mean diffusivity without covariates, but heterozygous carriers also showed regional decreases in mean diffusivity. A significant longitudinal increase in mean diffusivity was observed in non-carriers in the left inferior fronto-occipital fasciculus in the covariate-adjusted analysis. Other results were not significant after adding covariates. It cannot be concluded that apolipoprotein E ε4 affects longitudinal white matter microstructure in this study population. However, there are limitations in this study that could alter the interpretation of these results.