Design Considerations for Clinical Trials Combining Music Therapy and Physical Activity in Alzheimer’s Disease: Lessons from designing a Multicenter Randomized Protocol

Abstract

Non-pharmacological interventions targeting cognitive decline are increasingly important in aging and Alzheimer’s disease (AD). Music therapy and physical activity have both demonstrated neurocognitive and emotional benefits, but few studies have systematically explored their combined effects or the methodological challenges in implementing such interventions. This brief report discusses key design considerations for clinical trials integrating music and exercise in individuals with subjective cognitive decline (SCD), drawing on lessons from a multicenter, two-arm randomized controlled trial currently evaluating the addition of active music therapy to physical activity in older adults. Core design elements include careful population selection within the pre-dementia spectrum, standardized intervention delivery, culturally adapted musical stimuli, cluster randomization to reduce contamination, and the use of sensitive, multidomain cognitive outcomes. Methodological recommendations address standardization, adherence, control conditions, and statistical strategies appropriate for multicountry behavioral interventions. Integrating multimodal interventions such as music and exercise provides a novel framework for preventive neuroscience and rehabilitation, fostering cognitive resilience through synergistic engagement of motor, emotional, and memory circuits.