Cerebral microvascular changes in healthy carriers of the APOE-ε4 Alzheimer’s disease risk gene

APOE-ε4 is a genetic risk factor for Alzheimer’s Disease (AD). AD is associated with reduced cerebral blood flow (CBF) and with microvascular changes that limit the transport of oxygen from blood into brain tissue: reduced microvascular cerebral blood volume and high relative transit time heterogeneity (RTH). Healthy APOE-ε4 carriers reveal brain regions with elevated CBF compared to carriers of the common ε3 allele. Such asymptomatic hyperemia may reflect microvascular dysfunction: a vascular disease entity characterized by suboptimal tissue oxygen uptake, rather than limited blood flow per se. Here, we used perfusion MRI to show that elevated regional CBF is accompanied by reduced CBV in healthy APOE-ε4 carriers (carriers) aged 30-70 compared to similarly aged APOE-ε3 carriers (non-carriers). Younger carriers have elevated hippocampal RTH and more extreme RTH values throughout both white matter (WM) and cortical gray matter (GM) compared to non-carriers. Older carriers have reduced WM CBF and more extreme GM RTH values than non-carriers. Across all groups, lower WM and hippocampal RTH correlate with higher educational attainment, which is associated with lower AD risk. Three days of dietary nitrate supplementation increased carriers’ WM CBF but caused older carriers to score worse on two of six aggregate neuropsychological scores. The intervention improved late recall in younger carriers and in non-carriers. The APOE-ε4 gene is associated with microvascular changes that may impair tissue oxygen extraction. We speculate that vascular risk factor control is particularly important for APOE-ε4 carriers’ healthy aging.