Reduced cerebrovascular reactivity in young adults carrying the APOE ε4 allele

Abstract Background Functional magnetic resonance imaging (MRI) studies have shown that APOE ε2‐ and ε4‐carriers have similar patterns of blood‐oxygenation‐level‐dependent (BOLD) activation suggesting that we need to look beyond the BOLD signal to link APOE' s effect on the brain to Alzheimer's disease (AD)‐risk. Methods We evaluated APOE ‐related differences in BOLD activation in response to a memory task, cerebrovascular reactivity using a CO 2 ‐inhalation challenge (CO 2 ‐CVR), and the potential contribution of CO 2 ‐CVR to the BOLD signal. Results APOE ε4‐carriers had the highest task‐related hippocampal BOLD signal relative to non‐carriers. The largest differences in CO 2 ‐CVR were between ε2‐ and ε4‐carriers, with the latter having the lowest values. Genotype differences in CO 2 ‐CVR accounted for ∼70% of hippocampal BOLD differences between groups. Conclusion Because CO 2 ‐CVR gauges vascular health, the differential effect of APOE in young adults may reflect a vascular contribution to the vulnerability of ε4‐carriers to late‐life pathology. Studies confirming our findings are warranted.