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

Abstract Reduced cerebral blood flow occurs early in the development of Alzheimer’s disease (AD), suggesting an impairment in how the brain maintains its energy supply may contribute to disease onset. The ε4 allele of the Apolipoprotein (APOE) gene, the strongest risk factor for late onset AD, alters cerebrovascular function, increasing blood-brain barrier permeability. However, reports are mixed as to whether it affects cerebral blood flow regulation, and therefore could contribute to the altered cerebral blood flow observed early in disease. We hypothesised that APOE4 genotype increases risk of vascular dysfunction but requires additional factors to generate a significant reduction in the brain’s regulation of its blood supply that could promote dementia. To test this, we asked whether a modifiable lifestyle factor, physical activity, affected cerebrovascular and neuronal function in APOE3 and 4 targeted replacement (TR) mice. We used in vivo two-photon microscopy and haemodynamic measures to record neurovascular function from the visual cortex of APOE3 and APOE4-TR mice that were physically active or sedentary. Energy supply and demand were mismatched in APOE4 mice, with smaller increases in cerebral blood flow, blood volume and blood oxygenation observed during neuronal activation as blood vessels failed to adequately respond to increased neuronal energy needs. Exercise dose-dependently overall improved neurovascular function, with an increased impact of exercise apparent at later ages. Several haemodynamic measures showed a larger beneficial effect of exercise in APOE4 vs. APOE3 mice. Thus, APOE4 genotype in conjunction with sedentary behaviour produced the worst neurovascular function, which was improved by physical activity. Our results support the requirement for APOE4 genotype to combine with other factors to produce large deficits in cerebrovascular function and suggest that promotion of physical activity may be particularly important to improve cerebrovascular function and potentially to reduce dementia risk in APOE4 carriers.