Joint effects of sleep behaviors and physical activity on brain structure and cognitive function

Sleep behaviors and physical activity (PA) are widely used to predict the risk of neurodegenerative disease. However, how sleep and PA interact to influence brain and cognitive health remains unknown. This study investigated independent, joint, and interacting associations of sleep behaviors and PA with brain structures and cognitive phenotypes using linear regression and generalized linear models among over 40,000 middle-aged and older participants in UK Biobank. We first found that unhealthy sleep patterns, abnormal sleep duration and high levels of PA were each associated with worse cognitive function and brain structure damage. Joint association analyses revealed that the group with long sleep duration and low levels of PA had the greatest prevalence of white matter hyperintensities (WMH; β = 0.131, P _FDR = 0.013), a key metric of brain structural changes. Interestingly, interaction analysis suggested that a high level of PA significantly mitigates brain damage in relation to long sleep duration (i.e., grey matter loss, β _{moderate-long} = -0.088, β _high-long = -0.013, P _interaction = 0.024). In terms of cognitive phenotypes, a combination of long sleep and low levels of PA was similarly associated with worse cognitive performance (i.e., symbol digit scores, β = -0.043, P _FDR = 0.018). Additionally, when stratified by PA levels, long sleep duration exhibited a negative impact on cognition compared to normal sleep duration among those with low PA, but this effect was smaller or insignificant for those engaging in moderate or high PA (i.e., symbol digit scores, β _low-long = -0.047, P _FDR = 0.029; β _{moderate-long} = -0.022, P _FDR = 0.025; β _high-long = -0.016, P _FDR = 0.239). Overall, maintaining a high PA level during late middle age could potentially mitigate the detrimental effects on brain structure associated with excessive sleep. Healthy sleep habits alongside an adequate PA level are essential for maintaining brain health during aging.