Physical activity is associated with lower risks of developing dementia, Parkinson’s disease (PD) and depression. Furthermore, being physically active prior to brain ischemia appears to help the recovery process. However, previous studies do not differentiate between the two most common forms of dementia, Alzheimer’s disease (AD) and vascular dementia (VaD), when it comes to the association between physical activity and dementia. Also, these studies do not take into consideration the potential bias due to reverse causation when assessing these associations. Moreover, little is known about how exercise affects neuroinflammation and other pathological hallmarks of brain ischemia and AD.In this thesis, I investigate the potential of physical activity to act as a preventive strategy against common disorders affecting the brain. With a focus on translational medicine, I combined an epidemiological approach with experimental approaches. By using the Vasaloppet Registry together with the Swedish population and patient registries, we investigated if physically active skiers (n= 197,685) had lower risks of AD, VaD, PD and depression compared to an age and sex-matched general population (n=197,684) during an up to 21-year follow-up. Using experimental interventions, I investigated how running affected neuroinflammation and other aspects of the molecular pathology in mouse models of brain ischemia and AD.I discovered that forced running in mice prior to global brain ischemia may induce a stress response, leading to increased neuronal death in the hippocampus.We observed a lower risk of depression among both sex in our skiers (hazard ratio (HR)=0.50 (0.46-0.53), p<0.001). Among men, faster skiing was associated with an even lower risk compared to slower skiers (HR=0.65 (0.49-0.87), p=0.004), whereas faster female skiers did not have any difference in risk compared to slower counterparts (HR=1.14 (0.77-1.70), p=0.51). The reasons behind these differences require further investigation.Skiers also had a lower risk of developing PD compared to controls during the early follow-up period (HR=0.71 (0.55- 0.90), p=0.004), but this association became non-significant in sensitivity-analysis excluding persons diagnosed with PD within the first 5 years after inclusion (HR=0.80 (0.62-1.03), p=0.09). With longer follow-up times, the skiers’ cumulative PD incidence converged with that of the general population. These findings are in line with the motor reserve hypothesis, wherein physically active individuals may develop a motor reserve, allowing them to sustain PD pathology longer before symptoms appear.Moreover, skiers had a lower risk of VaD (HR=0.54 (0.37-0.80), p=0.002), but not AD (HR=0.88 (0.66-1.18), p=0.40). Experimentally, in the 5xFAD mouse model, 6 months of voluntary wheel running did not ameliorate their AD-like pathology. These findings question the general view of exercise as being protective against AD.Taken together, even though it is not equally effective against all disorders, a physically active lifestyle seems to be associated with a lower risk of developing disorders affecting the brain. Furthermore, the exact mechanisms behind these associations remain to be elucidated, and the optimal exercise settings need to be defined.