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
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, cognitivel...
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Frontiers Media S.A.
2025-05-01
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| author | Stephen M. Rao Alexandria L. Chorba M. J. Helppi Alina Tuladhar Amanda L. Penko Sarah Holley Brandon Nehls Sabrina Paulino Matthew C. Streicher Audrey Zhu Kellie Bruening Sally Durgerian Katherine Koenig Mark Lowe Wanyong Shin Stephen E. Jones Rachel Galioto Jagan A. Pillai Lynn M. Bekris James B. Leverenz Anson B. Rosenfeldt Tamanna Singh Gerald J. Beck J. Carson Smith Jay Alberts Jay Alberts |
| author_facet | Stephen M. Rao Alexandria L. Chorba M. J. Helppi Alina Tuladhar Amanda L. Penko Sarah Holley Brandon Nehls Sabrina Paulino Matthew C. Streicher Audrey Zhu Kellie Bruening Sally Durgerian Katherine Koenig Mark Lowe Wanyong Shin Stephen E. Jones Rachel Galioto Jagan A. Pillai Lynn M. Bekris James B. Leverenz Anson B. Rosenfeldt Tamanna Singh Gerald J. Beck J. Carson Smith Jay Alberts Jay Alberts |
| author_sort | Stephen M. Rao |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7906797e7fc844ceb7a8f23ffb82ce5a |
| institution | DOAJ |
| issn | 1663-4365 |
| language | English |
| publishDate | 2025-05-01 |
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| series | Frontiers in Aging Neuroscience |
| spelling | doaj-art-7906797e7fc844ceb7a8f23ffb82ce5a2025-08-20T03:12:32ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652025-05-011710.3389/fnagi.2025.15841151584115Protocol of a randomized, single-blind, controlled trial of an 18-month, home-based, high-intensity, exercise intervention in older, cognitively unimpaired APOE ε4 carriersStephen M. Rao0Alexandria L. Chorba1M. J. Helppi2Alina Tuladhar3Amanda L. Penko4Sarah Holley5Brandon Nehls6Sabrina Paulino7Matthew C. Streicher8Audrey Zhu9Kellie Bruening10Sally Durgerian11Katherine Koenig12Mark Lowe13Wanyong Shin14Stephen E. Jones15Rachel Galioto16Jagan A. Pillai17Lynn M. Bekris18James B. Leverenz19Anson B. Rosenfeldt20Tamanna Singh21Gerald J. Beck22J. Carson Smith23Jay Alberts24Jay Alberts25Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, United StatesCenter for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, United StatesCenter for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, United StatesCenter for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United StatesCenter for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, United StatesCenter for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, United StatesCenter for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, United StatesConcussion Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Diagnostic Radiology, Imaging Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Diagnostic Radiology, Imaging Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Diagnostic Radiology, Imaging Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Diagnostic Radiology, Imaging Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Diagnostic Radiology, Imaging Institute, Cleveland Clinic, Cleveland, OH, United StatesMellen Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United StatesCenter for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, United StatesLerner Research Institute, Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, United StatesCenter for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United StatesDepartment of Kinesiology, School of Public Health, University of Maryland, College Park, MD, United StatesDepartment of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United StatesConcussion Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United StatesBackgroundThe 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.https://www.frontiersin.org/articles/10.3389/fnagi.2025.1584115/fullAlzheimer’s diseaseexerciseneuroprotectionAPOE ε4randomized clinical trial |
| spellingShingle | Stephen M. Rao Alexandria L. Chorba M. J. Helppi Alina Tuladhar Amanda L. Penko Sarah Holley Brandon Nehls Sabrina Paulino Matthew C. Streicher Audrey Zhu Kellie Bruening Sally Durgerian Katherine Koenig Mark Lowe Wanyong Shin Stephen E. Jones Rachel Galioto Jagan A. Pillai Lynn M. Bekris James B. Leverenz Anson B. Rosenfeldt Tamanna Singh Gerald J. Beck J. Carson Smith Jay Alberts Jay Alberts 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 Frontiers in Aging Neuroscience Alzheimer’s disease exercise neuroprotection APOE ε4 randomized clinical trial |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Alzheimer’s disease exercise neuroprotection APOE ε4 randomized clinical trial |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1584115/full |
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