PROJECT SUMMARY The cascade of pathological changes involved in Alzheimer’s disease (AD) starts many years before AD diagnosis, suggesting that intervening with still-healthy adults will be most successful. According to the influential amyloid hypothesis, an imbalance between β-amyloid (Αβ) production and clearance initiates changes that lead to AD. This hypothesis suggests that early intervention targeting Αβ levels should be particularly effective in preventing AD, but the field has yet to test this core prediction of the hypothesis. A major obstacle is the lack of safe and low-cost interventions that reduce Αβ. Initial findings (N = 108) from our recently completed heart rate variability (HRV) biofeedback clinical trial indicate that daily sessions attempting to increase (via resonance-frequency breathing) vs. decrease (via personalized strategies) heart rate oscillations have significant opposing outcomes on plasma Αβ levels. Resonance-frequency breathing reduced overall plasma Αβ levels in both younger and older adults, and, among adults aged 55-70, increased Αβ42/Αβ40 ratios, a biomarker of reduced amyloid deposition in the brain. In this stage II double-blinded randomized trial, we aim to test hypotheses regarding the mechanisms behind this result as well as cognitive outcomes in African-American and European-American adults aged 50-70. Participants will complete ten weeks of daily paced breathing sessions, randomized to either a resonance-frequency breathing or a random- paced breathing condition. We hypothesize that resonance-frequency breathing reduces plasma biomarkers of AD risk via two synergistic pathways: 1) afferent vagus nerve activity suppresses noradrenergic activity that stimulates Aβ production; and 2) heart rate oscillations increase cerebrospinal fluid (CSF) flow, increasing brain clearance of Aβ42 in adults in their 50’s and 60’s in whom glymphatic clearance is declining. We will model how pre/post intervention change in plasma AD biomarkers relates to biomarkers associated with each of these hypothesized pathways. Compared with European Americans, African Americans have higher AD risk and higher noradrenergic/sympathetic system activity. They therefore may particularly benefit from resonance- frequency breathing. Across ethnicities, reduced levels of Αβ should especially benefit adults in their 50’s and 60’s, in whom amyloid is starting to aggregate in the brain as glymphatic clearance becomes less effective. The initial aggregative Αβ form (oligomeric Αβ) interferes with synaptic plasticity, so we will assess how much participants in the two conditions improve their performance on cognitive tasks they practice daily for 10 weeks. This innovative project will serve as a foundation for future long-term clinical trials to test the potential of resonance-frequency breathing to slow cognitive decline and prevent AD by reducing Αβ.