Objective We aimed to investigate the association of cardiorespiratory fitness (CRF) with cognitive function and dementia risk, taking genetic predisposition for dementia into account.

Methods Within the UK Biobank, 61 214 dementia-free participants aged 39–70 years were followed for up to 12 years. CRF score was estimated using a 6 min submaximal exercise test on a stationary bike and divided into tertiles (ie, low, moderate, and high; standardised by age and sex). Global cognitive function was evaluated at baseline. Dementia was identified based on medical history and medical records. Genetic predisposition for dementia was estimated using the polygenic risk score for Alzheimer’s disease (PRS_AD), tertiled as low, moderate, or high. Data were analysed using linear regression, Poisson regression, and Laplace regression.

Results Compared with low CRF, high CRF was related to better global cognitive function (β=0.05, 95% CI 0.04 to 0.07). Over the follow-up period, 553 individuals developed dementia. Compared with low CRF, the incidence rate ratio (IRR) of all dementia was 0.60 (95% CI 0.48 to 0.76) for high CRF, and the onset of all dementia was delayed by 1.48 (95% CI 0.58 to 2.39) years among people with high versus low CRF. Among people with a moderate/high polygenic risk score, high CRF attenuated all dementia risk by 35% (IRR 0.65, 95% CI 0.52 to 0.83).

Conclusion High CRF is associated with better cognitive performance at baseline, and lower dementia risk long-term. High CRF could mitigate the impact of genetic predisposition on the development of dementia by 35%.