APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice

Reduced cerebral blood flow occurs early in the development of Alzheimer's disease (AD), but the factors producing this reduction are unknown. Here, we ask whether genetic and lifestyle risk factors for AD-the ε4 allele of the Apolipoprotein (APOE) gene, and physical activity-can together produce this reduction in cerebral blood flow which leads eventually to AD. Using in vivo two-photon microscopy and haemodynamic measures, we record neurovascular function from the visual cortex of physically active or sedentary mice expressing APOE3 and APOE4 in place of murine APOE. Energy supply and demand are mismatched in APOE4 mice, with smaller increases in cerebral blood flow, blood volume and blood oxygenation occurring during neuronal activation as blood vessels frequently fail to dilate. Exercise dose-dependently overall improves neurovascular function, with an increased impact of exercise apparent after longer exposure times. Several haemodynamic measures show a larger beneficial effect of exercise in APOE4 vs. APOE3 mice. Thus, APOE4 genotype in conjunction with sedentary behaviour produces the worst neurovascular function. Promotion of physical activity may therefore be particularly important to improve cerebrovascular function and reduce dementia risk in APOE4 carriers.