Nearly 61% of women with breast cancer experience a decline in cognitive function with adjuvant therapy. We found declines in attention and working memory with aromatase inhibitor (AI) therapy in women with breast cancer and poorer executive function compared to healthy controls. Multiple biological mechanisms likely underlie this cognitive decline including estrogen (E2) reduction and cytokine dysregulation. AI therapy provides near complete E2 withdrawal and we found that lower E2 levels were related to poorer psychomotor efficiency, attention and executive function with breast cancer therapy. Increases in pro- inflammatory cytokines occur with cancer and persist up to 5 years post-treatment. We found that higher IL-6 levels are related to poorer executive function and reduced gray matter volume. The effect of AIs on cognitive function may also be mediated by symptoms experienced by women with breast cancer including fatigue, sleep problems, depression and anxiety. A promising method for improving cognitive and brain function in older adults is moderate intensity aerobic exercise. Our neuroimaging studies have shown that only modest amounts of aerobic exercise increase hippocampal volume and modify intrinsic connectivity and task-related functional dynamics in the prefrontal cortex and hippocampus. We also found that exercise reduces pro- inflammatory cytokines that are directly linked to hippocampal size and memory formation. Exercise also reduces depression and anxiety and the severity of fatigue and sleep problems in women with breast cancer. We propose a clinical trial in which post-menopausal women with early stage breast cancer are randomized to receive a 6-month, moderate-intensity aerobic exercise intervention or usual care. We will examine whether a well-controlled and monitored site-based exercise intervention, initiated before AI therapy, improves cognitive function and explore whether neuroimaging metrics of brain health, pro-inflammatory biomarkers (IL-6, CRP, TNF-α), and symptoms (fatigue, sleep problems, depression, anxiety) mediate the effects of exercise on cognitive function. Furthermore, we will explore whether the magnitude of the improvements in cognitive function are modified by E2. The specific aims include: 1) Compared to usual care, examine whether the 6-month exercise intervention improves cognitive function over the first six months of AI therapy in postmenopausal women with early stage breast cancer. 2) Compared to usual care, examine the direct effects of exercise on neuroimaging metrics of brain health including regional gray matter volume, white matter architecture and functional dynamics of the brain and pro-inflammatory biomarkers (IL-6 and CRP as primary outcomes; TNF-α as secondary) and explore the direct effects of exercise on symptoms (fatigue, sleep problems, depression, anxiety). 3) Compared to usual care, explore whether the effects of exercise on cognitive function are mediated by neuroimaging metrics of cognitive function, pro-inflammatory cytokines and symptoms and moderated by E2.