Inactivity, sedentary behavior, and the risk for Alzheimer’s disease in middle aged to older adults

Abstract Alzheimer’s disease is a devastating progressive neurodegenerative disease that leads to a profound loss of brain and cognitive functions. There is an urgent need to identify factors that can decrease risk, including modifiable lifestyle behaviors. Exercise and physical activity (PA) have shown promise in reducing rates of cognitive decline, brain structural atrophy, and risk of developing Alzheimer’s disease and other related dementias. However, despite decades of work, and recommendations to improve exercise participation, levels of PA and engagement in purposeful exercise have not increased greatly. In contrast to PA, the effect of sedentary behavior (SB) or time spent sitting on Alzheimer’s disease risk has received less attention. SB may have independent physiological effects on health which may not be fully ameliorated by engaging in PA, and there is growing evidence that SB may have detrimental effects on cognition and brain structure. Understanding the effects of SB on Alzheimer’s disease risk may provide a key target for behavioral modification since reducing time spent sitting may be easier to implement compared to increasing exercise levels in older adults. In this proposal, we will determine whether time spent in SB is associated with brain health and the risk of developing Alzheimer’s disease and all-cause dementia. Here, we focus on the effects of SB on cognition, brain structure, and Alzheimer’s disease incidence in the largest prospective cohort analyzed to date, the UK Biobank. We will analyze associations between markers of SB including self-report and objective measures from wearable accelerometers, and cognition, brain health, and incident Alzheimer’s disease and all-cause dementia. This unique dataset will allow us to determine the best SB predictors of brain aging outcomes, including Alzheimer’s disease incidence so that interventions can focus on reducing the most harmful aspects of SB in older adults. Using this dataset along with three replication datasets, we will test our overarching hypothesis that high levels of SB are associated with increased cognitive decline, poorer brain health, and increased Alzheimer’s disease risk that is not fully mitigated by complementary engagement in PA. To test this hypothesis, this proposal will address the following specific aims: 1) to determine how SB is associated with incident Alzheimer’s disease and all-cause dementia, 2) to evaluate the cross-sectional and prospective relationships between SB and aspects of cognition and brain structure associated with Alzheimer’s disease risk, and 3) to investigate how displacing SB with time spent in different PA levels modifies the association between SB and Alzheimer’s disease risk. By evaluating a novel, comprehensive set of SB markers and testing their associations with cognition, brain structure, and Alzheimer’s disease risk, this proposal provides a unique opportunity to obtain key data needed to help advance efforts in developing effective interventions for Alzheimer’s disease prevention.