This study is a single-site, randomized, parallel-group clinical trial designed to evaluate both behavioral efficacy and mechanistic target engagement of high-velocity resistance training (HVRT) in older adults at elevated risk for Alzheimer's disease and related dementias (AD/ADRD). The trial is structured as an early-stage efficacy study consistent with a Stage IIA framework, with emphasis on testing a hypothesized physiological mechanism linking exercise to cognitive outcomes. A growing body of research suggests that vascular dysfunction may contribute to cognitive decline and dementia risk. Altered cerebrovascular regulation, including impaired neurovascular coupling, reduced dynamic cerebral autoregulation, and diminished cerebrovascular reactivity to carbon dioxide, has been observed in older adults and in individuals with vascular risk factors. These physiological impairments may limit the brain's ability to appropriately regulate blood flow during cognitive and physical demands. Exercise interventions may improve vascular function; however, the specific effects of high-velocity resistance training on cerebrovascular regulatory mechanisms and their relationship to cognitive performance remain insufficiently characterized. High-velocity resistance training emphasizes rapid concentric muscle actions performed against moderate external loads. This training approach is designed to improve neuromuscular power, which declines with aging and is strongly associated with functional mobility. HVRT may provide distinct hemodynamic and neurovascular stimuli compared to traditional resistance training due to the speed of contraction and associated pressor responses. This study will test whether a 12-week supervised HVRT intervention produces measurable improvements in executive function, processing speed, and motor-cognitive performance, and whether such improvements are associated with changes in cerebrovascular regulation. Participants will be randomized in a 1:1 ratio to either the HVRT intervention or a waitlist control condition. The intervention consists of three supervised sessions per week for 12 weeks, using progressive loading phases spanning approximately 40 to 80 percent of one-repetition maximum. All training sessions are conducted in person under the supervision of trained exercise professionals following standardized operating procedures. The waitlist control group will maintain usual activities during the 12-week period and will be offered the exercise program after completing post-intervention testing. Cognitive and motor-cognitive performance will be assessed under both single-task (seated) and dual-task (treadmill walking) conditions to evaluate cognitive function under varying levels of physiological demand. Dual-task paradigms are included to probe real-world motor-cognitive integration and to assess whether exercise-related adaptations extend to functionally relevant conditions. Cerebrovascular regulation will be assessed non-invasively using transcranial Doppler ultrasound to measure cerebral artery blood flow velocity. Continuous electrocardiography, beat-to-beat blood pressure monitoring, and end-tidal carbon dioxide measurement will be recorded concurrently to permit integrated physiological modeling. Neurovascular coupling will be evaluated as the change in cerebral blood flow velocity during cognitive activation. Dynamic cerebral autoregulation will be assessed using oscillatory lower-body negative pressure protocols to induce controlled blood pressure fluctuations. Cerebrovascular reactivity will be assessed using a standardized hypercapnic rebreathing procedure to quantify the cerebral blood flow response to elevated carbon dioxide levels. Primary analyses will examine group-by-time interaction effects on cognitive performance. Secondary analyses will evaluate changes in neurovascular coupling, dynamic cerebral autoregulation, and cerebrovascular reactivity. Exploratory analyses will estimate whether changes in cerebrovascular regulation statistically mediate intervention-related improvements in cognitive outcomes and whether biological sex moderates these associations. These mechanistic analyses are intended to inform the design of future fully powered efficacy trials. This study will contribute to understanding whether a scalable, supervised resistance training intervention can engage cerebrovascular mechanisms linked to cognitive performance in older adults at elevated dementia risk. Findings may inform the development of targeted exercise-based strategies to support brain health in aging populations.
