PROJECT SUMMARY Aging is the primary risk factor for Alzheimer’s disease and related dementias, as well as mild cognitive impairment (MCI). Above-normal systolic blood pressure (SBP; ≥120 mmHg) further increases risk of dementias, due, in part, to SBP-associated cerebrovascular dysfunction, i.e., impaired cerebral blood flow regulation. Accordingly, midlife and older adults with above-normal SBP are at the highest risk for cognitive decline driven by vascular contributions to cognitive impairment and dementias in this age group. Excessive reactive oxygen species-induced oxidative stress and reductions in nitric oxide (NO) bioavailability within the cerebral vasculature likely mediate cerebrovascular dysfunction with aging and contribute to MCI and Alzheimer’s disease and related dementias in those with above-normal SBP. Passive heat therapy (regular short-term increases in body core temperature) is an established lifestyle practice in certain cultures (e.g., sauna bathing in Finland; hot spring bathing in Japan) and may be effective for decreasing risk of dementias. Epidemiological research suggests regular sauna use is associated with ~65% lower incidence of dementias, supporting heat therapy as a powerful candidate approach to significantly reduce risk of dementias. However, randomized controlled trials are urgently needed to establish the causal link between passive heat therapy and risk factors for MCI, Alzheimer’s disease and related dementias. Results from our pilot trial show that 8-10 weeks of heat therapy (hot water immersion 3x1 h/week) lowered SBP (-10 mmHg) and improved cognitive performance and cerebrovascular function vs. sham (thermoneutral water immersion). Heat therapy also reduced vascular markers of oxidative stress and increased NO bioavailability. Our parent award is a randomized clinical trial assessing 3 months (36 x 1 h sessions) of passive heat therapy vs. sham immersion for lowering SBP and improving peripheral vascular function in midlife and older adults with SBP 120-139 mmHg. This proposal will extend the work of our parent grant by assessing the efficacy of heat therapy for: 1) increasing key domains of cognitive performance; 2) improving cerebrovascular blood flow and other measures of cerebrovascular function and health that are closely linked to MCI and dementias; and 3) decreasing oxidative stress and increasing NO-bioavailability, important mechanisms likely underlying cognitive impairment and dementias. This research is highly relevant to MCI and Alzheimer’s disease and related dementias, as it will evaluate a novel lifestyle-based therapy for improving key risk factors for these disorders. Leveraging our existing clinical trial, we will provide the first evidence for the efficacy of passive heat therapy for enhancing cognitive and cerebrovascular function in older adults at risk of developing MCI and Alzheimer’s disease and related dementias. Lastly, the proposed research will also stimulate future research pr...