BACKGROUND: Physical activity provides benefits against cognitive decline but its associations with Alzheimer's disease pathophysiology are not fully understood. We investigated cross-sectional and longitudinal associations between moderate-to-vigorous physical activity and phosphorylated (p)-tau181 blood concentrations, and the role of p-tau181 in the associations between moderate-to-vigorous physical activity and cognition. METHODS: In this post-hoc secondary analysis, we used data from a multicentre, randomised, placebo-controlled superiority trial (the Multidomain Alzheimer's Preventive Trial [MAPT]), in which adults aged 70 years and older were recruited from the community in 13 memory centres in France and Monaco. Individuals were eligible if they met at least one of the following criteria: spontaneous memory complaints, low gait speed (≤0·77 m/s), or limitation in at least one instrumental activity of daily living. Exclusion criteria included a dementia diagnosis, a Mini Mental State Examination score below 24, and having limitations in basic activities of daily living. For this secondary analysis, participants from MAPT were included if they had blood p-tau181 concentrations measured at baseline or at 3 years, or both timepoints. Self-reported moderate-to-vigorous physical activity (in metabolic equivalent of task min per week) and a cognitive composite score (calculated by averaging the Z scores of four cognitive tests) were assessed at baseline and at 6 months and at 1, 2, and 3 years. Mixed-effect models were used to examine the cross-sectional and longitudinal associations between moderate-to-vigorous physical activity and p-tau181 concentrations and to explore the mediating and moderating role of p-tau181 concentration on the association between moderate-to-vigorous physical activity and cognition. FINDINGS: Between May 30, 2008, and Feb 24, 2011, 1679 individuals were enrolled in the MAPT, of whom 558 adults had measurements of p-tau181 concentrations at baseline, 3 years, or both timepoints. Higher levels of moderate-to-vigorous physical activity were associated with slower changes in p-tau181 concentrations over time. Compared with inactive individuals, those with low levels of activity (low moderate-to-vigorous physical activity × time: B = -0·109 [95% CI -0·206 to -0·012
p=0·028]) or high levels of activity (high moderate-to-vigorous physical activity × time: B=-0·114 [95% CI -0·208 to -0·020
p=0·018) had a slower increase in p-tau181 concentrations. We did not identify any association between baseline p-tau181 concentrations and baseline moderate-to-vigorous physical activity levels. The cross-sectional and longitudinal associations between moderate-to-vigorous physical activity and cognition were attenuated with increasing baseline p-tau181 concentrations. Specifically, moderate-to-vigorous physical activity was no longer favourably associated with the cognitive composite score when baseline p-tau181 concentration exceeded 9·36 pg/mL and 3·5 pg/mL for the cross-sectional association and longitudinal association, respectively. INTERPRETATION: Our findings suggest that engaging in more moderate-to-vigorous physical activity might help to slow the age-related neurodegenerative process, although p-tau pathophysiology seems to mitigate the beneficial associations between moderate-to-vigorous physical activity and cognition in older adults. Verification of these findings in larger population samples will be needed. FUNDING: Toulouse Gérontopôle, French Ministry of Health, and Pierre Fabre Research Institute.