PROJECT SUMMARY This application is in response to NOT-AG-21-018, Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s disease. Aging is the primary risk factor for mild cognitive impairment and Alzheimer’s disease. Women make up two thirds of all Alzheimer’s disease diagnoses. Specifically, postmenopausal (PM) women with above-normal systolic blood pressure (SBP ≥120 mmHg), i.e., >75% of PM women in the U.S., are at the highest risk for mild cognitive impairment and dementias. A primary mechanism linking above-normal SBP to cognitive decline is cerebrovascular dysfunction, i.e., impaired cerebral blood flow regulation, which is mediated by excessive reactive oxygen species (ROS)- induced oxidative stress and reductions in nitric oxide (NO) bioavailability within the cerebrovasculature. Aerobic exercise (AE) is a first-line intervention for lowering SBP that can reduce the risk of mild cognitive impairment and Alzheimer’s disease. However, in PM women with above-normal SBP, AE only decreases casual (resting) SBP by ~3 mmHg and is ineffective at improving cerebrovascular function. In addition, only 25- 30% of PM women meet guidelines for 150 min/week of moderate-intensity AE, often due to a lack of time. High-resistance inspiratory muscle strength training (IMST) is a novel, time-efficient lifestyle intervention that involves 30 inhalations/session against a resistive load using a portable hand-held device – a program that requires only ~5 min/day. Results from the PM women in our NIA R21-funded pilot trial show that 6 weeks of IMST (6 days/week) promoted adherence (94% of sessions completed), lowered SBP (-7 mmHg) and improved episodic memory (domain of cognition closely linked to mild cognitive impairment/Alzheimer’s disease) and cerebrovascular function vs. sham (low-resistance inhalation) training. IMST also changed systemic circulating factors that reduced oxidative stress and increased NO bioavailability in endothelial cells. Our parent award is a randomized clinical trial assessing 3 months of high-resistance IMST vs. moderate- intensity AE for lowering SBP in PM women with above-normal SBP. We propose to extend our parent trial to assess IMST for improving episodic memory and other cognitive domains closely linked to mild cognitive impairment and dementia, and for improving cerebrovascular function by decreasing oxidative stress and increasing NO bioavailability. This research is highly relevant to Alzheimer’s disease and related dementias as it will evaluate a novel time-efficient lifestyle intervention for improving cognitive function and established mild cognitive impairment/Alzheimer’s disease risk factors in asymptomatic at-risk PM women with above- normal SBP, a group disproportionately burdened by Alzheimer’s disease. Leveraging our ongoing clinical trial will stimulate research regarding Alzheimer’s disease and related dementias by providing initial evidence for the efficacy of IMST for ...