Abstract: Aerobic exercise (AE) is one of the most promising, accessible, and cost-effective methods for reducing risk for Alzheimer's disease (AD) and related dementias (ADRD), and for improving brain health and cognition in older adults. However, we do not fully understand the mechanisms by which AE-induced changes in the brain improve cognition and reduce the likelihood of transitioning to cognitive impairment. Cerebrovascular alterations progress with aging and have been identified as one of the primary factors associated with cognitive decline. Therefore, one leading hypothesis is that AE can modify aging-associated cerebrovascular deteriorations by accumulating long-term adaptations through repeated training sessions. These cerebrovascular changes could mediate improvements in structure and function in the brain, and associate with cognitive improvement. However, we still do not fully understand these possible mechanisms, nor the most effective doses to maximize cerebrovascular improvements. In order to assess cerebrovascular changes and their relationship with structural and functional brain changes in response to an AE intervention, we propose to conduct a secondary data analysis using a Phase III randomized clinical trial (RCT) of aerobic exercise called Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE). The IGNITE study included pre- and post-intervention assessments from a 12-month supervised exercise intervention in 648 cognitively normal adults between 65 and 80 years of age. Participants were randomized to one of 3 different dosage groups (n=213 each): (i) a moderate intensity AE of 150 min/week (the public-health recommended dose), (ii) a moderate intensity AE condition of 225 min/week, and (iii) a stretching control condition of 150 min/ week. We will test (1) whether a 12-month RCT of AE modifies cerebrovascular pulsatility and blood flow and whether these changes mediate improvements in cognition, (2) whether AE- induced cerebrovascular changes mediate improvements in brain atrophy, functional connectivity, and reduce WMH growth. We will also test whether any effects are associated with pre-existing health status, such as hypertension and type2 diabetes, which are associated with risk for AD/ADRD and linked to AD pathology (e.g. Ab and tau) . We will also examine whether biological sex moderates the results found in aims 1 and 2. We hypothesize that the group receiving 225 min/week will show the greatest cerebrovascular improvements and that these improvements mediate structural and functional brain changes. We also expect that the cerebrovascular improvements with AE will occur in region-specific manner and lead to domain-specific cognitive improvements that are related to those areas. This proposal employs a highly cost-effective approach by focusing on the secondary data analysis of an NIH-funded RCT and is therefore in line with the NIA mission to use data from existing cohorts to address im...