ABSTRACT: BACKGROUND:Physical activity might reduce the risk of developing dementia. However, it is still unclear whether the protective effect differs depending on the subtype of dementia. We aimed to investigate if midlife physical activity affects the development of vascular dementia (VaD) and Alzheimer's disease (AD) differently in two large study populations with different designs. METHODS:Using a prospective observational design, we studied whether long-distance skiers of the Swedish Vasaloppet (n?=?197,685) exhibited reduced incidence of VaD or AD compared to matched individuals from the general population (n?=?197,684) during 21?years of follow-up (median 10, interquartile range (IQR) 5-15?years). Next, we studied the association between self-reported physical activity, stated twice 5?years apart, and incident VaD and AD in 20,639 participants in the Swedish population-based Malmo Diet and Cancer Study during 18?years of follow-up (median 15, IQR 14-17?years). Finally, we used a mouse model of AD and studied brain levels of amyloid-?, synaptic proteins, and cognitive function following 6?months of voluntary wheel running. RESULTS:Vasaloppet skiers (median age 36.0?years [IQR 29.0-46.0], 38% women) had lower incidence of all-cause dementia (adjusted hazard ratio (HR) 0.63, 95% CI 0.52-0.75) and VaD (adjusted HR 0.49, 95% CI 0.33-0.73), but not AD, compared to non-skiers. Further, faster skiers exhibited a reduced incidence of VaD (adjusted HR 0.38, 95% CI 0.16-0.95), but not AD or all-cause dementia compared to slower skiers. In the Malmo Diet and Cancer Study (median age 57.5?years [IQR 51.0-63.8], 60% women), higher physical activity was associated with reduced incidence of VaD (adjusted HR 0.65, 95% CI 0.49-0.87), but not AD nor all-cause dementia. These findings were also independent of APOE-?4 genotype. In AD mice, voluntary running did not improve memory, amyloid-?, or synaptic proteins. CONCLUSIONS:Our results indicate that physical activity in midlife is associated with lower incidence of VaD. Using three different study designs, we found no significant association between physical activity and subsequent development of AD.
