Structural and resting-state MRI detects regional brain differences in young and mid-age healthy APOE-e4 carriers compared to non-APOE-e4 carriers

The presence of the e4 allele of apolipoprotein E (APOE) gene is the best known genetic risk factor for Alzheimer’s disease. In this study we investigated the link between functional and behavioural differences and regional brain volume and cortical thickness differences between those that carry the e4 allele (e4+) and those that only carry the e3 allele (e3/e3). We studied these genotype populations in two age groups: a young group (average age 21 years); and a mid-age group (average age 50 years). High-resolution T1-weighted MRI scans were analyzed with Freesurfer to measure regional white matter brain volume and cortical thickness differences between genotype groups at each age. This data was correlated against behavioural findings on the same cohort. Resting-state MRI was also conducted to identify differences in underlying brain functional connectivity. We found that there is a positive correlation between the thickness of the parahippocampal cortex in young e4+ and performance on an episodic memory task. Young e4+ also showed a positive correlation between white matter volume in the left anterior cingulate and performance on a covert attention task. At mid age, e4+ had structural differences compared to e3/e3 in these areas: the parahippocampal cortex was thicker and white matter volume in the left anterior cingulate was greater than e3/e3. We discuss the possibility that an over-engagement with these regions by e4+ in youth may have a neurogenic effect that is observable later in life. The cuneus appears to be an important region for APOE-driven differences in the brain, with greater functional connectivity among young e3/e3 and greater white matter volume in the young e4+.