Abstract
Historically regarded as a hub for autonomic control, the brainstem is now increasingly recognized for its role in cognition. However, little information is available regarding its specific contribution to cognitive function, particularly in midlife, when modifiable cardiovascular risks begin to shape brain health trajectories. Because the brainstem houses key nuclei that regulate cardiovascular dynamics and cerebral perfusion, we focused on carotid-femoral pulse wave velocity (cfPWV), a well-established index of central arterial stiffness that directly reflects cerebral hemodynamic load. This study investigated whether brainstem volume is associated with cognitive performance in healthy midlife adults and whether this relation is moderated by cfPWV. A total of 198 adults aged 40-65 years underwent neuropsychological testing, fasting cardiovascular and metabolic assessments, and structural MRI. Linear regression models examined brainstem volume as a predictor of attention, executive function, and memory, adjusting for age, sex, education, and total intracranial volume. Additional models tested the interaction between cfPWV and brainstem volume, controlling for cardiometabolic covariates. Greater brainstem volume was significantly associated with better memory performance (p = .010, FDR q = 0.030), but not attention or executive function. Greater brainstem volume was also associated with lower systolic and pulse pressure. Notably, cfPWV moderated the relationship between brainstem volume and memory, such that the positive association was strongest among individuals with higher arterial stiffness (p = .001, FDR q = 0.002). These findings suggest that the brainstem may serve as a structural hub linking peripheral vascular health and cognitive function in midlife, particularly under conditions of elevated arterial stiffness.