Physical activity and combinations with modifiable factors and risk of cognitive impairment: the Whitehall II study

INTRODUCTION Physical activity is a key modifiable protective factor for cognitive health, but randomized controlled trials initiating physical activity in late life have often failed to demonstrate significant cognitive benefits. The optimal window for prevention may be midlife, before irreversible pathology is established. We emulated a target trial to estimate counterfactual risks of cognitive impairment under hypothetical strategies of initiating or maintaining physical activity, alone or in combination with lifestyle and vascular risk modifications from midlife. METHODS We utilized data from the Whitehall II study ( n = 3011) with baseline ages 45 to 64, following participants from midlife for up to 18 years. We applied the parametric g‐formula to handle time‐varying confounding and emulate hypothetical interventions. Strategies included physical activity, alone or combined with modifications to diet, smoking, alcohol consumption, and vascular risk modification (systolic blood pressure, total cholesterol, fasting glucose, and body mass index). The primary outcome was cognitive impairment based on cognitive tests. One thousand sets of bootstrapping were conducted to obtain 95% confidence intervals (CIs). RESULTS Initiating physical activity alone did not significantly reduce the 18‐year cumulative incidence of cognitive impairment. However, the estimated risk of cognitive impairment was lower under the strategy combining physical activity with healthy diet and no smoking, and with normal body mass index, compared with the natural course. Also, comprehensive strategies targeting physical activity, lifestyle factors, and all vascular risk factors achieved significant risk reduction. DISCUSSION While physical activity initiated in midlife may be insufficient as a single intervention in this cohort, its integration into a comprehensive multidomain strategy addressing lifestyle and vascular health significantly reduces the risk of cognitive impairment. These findings support holistic prevention strategies from midlife to improve long‐term cognitive outcomes.