AUTHOR=Rao Stephen M. , Chorba Alexandria L. , Helppi M. J. , Tuladhar Alina , Penko Amanda L. , Holley Sarah , Nehls Brandon , Paulino Sabrina , Streicher Matthew C. , Zhu Audrey , Bruening Kellie , Durgerian Sally , Koenig Katherine , Lowe Mark , Shin Wanyong , Jones Stephen E. , Galioto Rachel , Pillai Jagan A. , Bekris Lynn M. , Leverenz James B. , Rosenfeldt Anson B. , Singh Tamanna , Beck Gerald J. , Smith J. Carson , Alberts Jay 

TITLE=Protocol of a randomized, single-blind, controlled trial of an 18-month, home-based, high-intensity, exercise intervention in older, cognitively unimpaired APOE ε4 carriers

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 17 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2025.1584115

DOI=10.3389/fnagi.2025.1584115

ISSN=1663-4365

ABSTRACT=BackgroundThe World Health Organization highlighted the potential protective role of exercise against cognitive decline, all-cause dementia, Alzheimer’s disease (AD), and vascular dementia in healthy individuals. We have previously shown that exercise is particularly beneficial for older, cognitively unimpaired apolipoprotein E4 (APOE ε4) carriers. A key unanswered question is whether a long-term, high-intensity aerobic exercise intervention initiated in a cohort of previously inactive older individuals at genetic risk for AD has neuroprotective properties.DesignCYCLE-AD is a randomized, single-blind, single-center, controlled trial of a home-based, high-intensity exercise intervention involving 150 older ε4 carriers (ages 65–80 years) who are healthy, cognitively unimpaired, and physically inactive. Participants are randomized into two groups: indoor cycling (IC) or usual and customary care (UCC) (target of 75 each). IC participants exercise 3×/week on an upright stationary cycle ergometer at a moderate-vigorous intensity for 18 months. Those in the UCC group are expected to maintain enrollment levels of activity.OutcomesComparison of IC and UCC groups on change in primary and secondary outcomes over baseline, 9-month, and 18-month evaluations. Primary outcomes are VO2peak (Fitness), 5-trial total recall on the Rey Auditory Verbal List Learning Test (Episodic Memory), and total hippocampal volume derived from structural MRI (Brain Atrophy). Secondary outcomes include comprehensive neurocognitive and physical function test batteries, MRI scans including structural and functional connectivity measures, and blood-based biomarkers.HypothesesOver an 18-month interval, physically inactive ε4 carriers who engage in high-intensity aerobic exercise will demonstrate less cognitive decline and hippocampal atrophy than physically inactive ε4 carriers who did not participate in a formal exercise program.ConclusionSuccessful demonstration of a scalable, home-based, high-intensity aerobic exercise intervention in altering the trajectory of AD pathophysiology and its effects on cognitive functioning will transform AD treatment, improve patient outcomes and quality of life, and reduce healthcare costs.