The absence of effective methods for treating age-relate cognitive decline presents a significant public health problem, considering its ubiquity with unprecedented increases in the aging population. Recently, lifestyle choices, particularly exercise, have been noted as potential effective strategies for maintaining and enhancing brain health and cognitive function in older adults. However, the public and scientific community is yet to reach agreements on the conclusive benefits of exercise on the brain. Currently a Phase III clinical trial: IGNITE (Investigating Gains in Neurocognition in an Intervention Trial of Exercise) is ongoing to address the ambiguity in influences of exercise on brain health and cognitive function in older adults. We propose an ancillary study to determine the impact of exercise on antioxidant status in the brain of participants drawn from IGNITE, in which clinical, imaging, genetic, molecular and physiological measures will be acquired. We will determine the association of antioxidant status with cognitive function and brain health as well as the impact of genetic and molecular risk factors of Alzheimer's disease (AD) on these relationships. Our long-term goal is 1) to identify the underlying mechanisms of improved brain health and cognitive performance associated with behavioral interventions and/or new targeted therapies in older adults, and 2) to offer novel possibilities for directly monitoring the impact of these emergent treatment options through new quantitative, non-invasive neuroimaging indices of brain health in aging, AD and AD-related diseases. Our overall hypothesis is that exercise enhances cerebral antioxidant defenses to fight against oxidative stress in the aging brain by increasing the levels of glutathione (GSH), which leads to improved brain health and cognitive function. GSH is a key component of the cerebral antioxidant system, which is consumed to protect cells against oxidative damage resulting in lower GSH levels in brain tissue. Our preliminary data suggest that brain GSH is related with the cognitive performance of older adults in multiple domains, lowered in aging and AD, and increases after exercise interventions. The Specific Aims are: (1) to determine the influence of exercise intervention on the brain antioxidant status in the aging brain, (2) to determine the mediating relationship between the brain antioxidant status and exercise-associated improvements in cognitive function and brain health, and (3) to examine modulating effects of genetic/molecular markers of Alzheimer's disease on changes in brain antioxidant status after exercise intervention. The expected outcome of this project is 1) the identification of a major mechanism, oxidative stress, underlying the beneficial effects of exercise on cognitive function and brain health seen in older adults, 2) the identification of a mechanism-based neuroimaging marker reflecting neuromodulating effects of exercise intervention and the dose-response effects, and 3) the identification of exercise intervention as an important strategy to enhance neuroprotection via increased cerebral antioxidant defenses.