Objective: To determine whether poor cardiovascular (CV) fitness and exaggerated exercise blood pressure (BP) and heart rate (HR) were associated with worse brain morphology in later life.

Methods: Framingham Offspring participants (n = 1,094, 53.9% female) free from dementia and CV disease (CVD) underwent an exercise treadmill test at a mean age of 40 ± 9 years. A second treadmill test and MRI scans of the brain were administered 2 decades later at mean age of 58 ± 8 years.

Results: Poor CV fitness and greater diastolic BP and HR response to exercise at baseline were associated with a smaller total cerebral brain volume (TCBV) almost 2 decades later (all p < 0.05) in multivariable adjusted models; the effect of 1 SD lower fitness was equivalent to approximately 1 additional year of brain aging in individuals free of CVD. In participants with prehypertension or hypertension at baseline, exercise systolic BP was also associated with smaller TCBV (p < 0.05).

Conclusion: Our results suggest that lower CV fitness and exaggerated exercise BP and HR responses in middle-aged adults are associated with smaller brain volume nearly 2 decades later. Promotion of midlife CV fitness may be an important step towards ensuring healthy brain aging.