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CYCLE-AD Trial: Testing High-Intensity Exercise to Stave Off Alzheimer’s Disease

With a new $6.7 million grant from NIH, Drs. Alberts and Rao will test if home-based, high-intensity cycling may help prevent sedentary adults who carry the highest risk Alzheimer’s-related gene variant from developing the disease.


The National Institute on Aging, part of the National Institutes of Health, has awarded Cleveland Clinic a five-year, $6.7 million grant to evaluate the effect of high-intensity exercise—using a home-based, internet-connected indoor cycle—on preventing Alzheimer’s disease (AD) in people at high genetic risk of the disease.

The randomized controlled trial, named CYCLE-AD (Cycling to Cease or Limit the Effects of Alzheimer’s Disease) is led by co-principal investigators Jay Alberts, PhD, staff in the Department of Biomedical Engineering, and Stephen Rao, PhD, staff in Cleveland Clinic’s Luo Ruvo Center for Brain Health.

A quest to slow AD progression

Prior to this grant, Dr. Rao’s research team conducted an 18-month observational study that found people who carry the APOE ε4 (apolipoprotein E epsilon 4) variant—the most important known genetic risk factor for late-onset AD—and were moderately active experienced significantly lower declines in episodic memory and hippocampal volume compared with carriers who were sedentary. No such exercise differences were observed in non-carriers, suggesting that exercise provides a unique benefit in slowing disease progression among people at genetic risk for AD.

“Slowing progression can make a huge difference in the quality of life of patients and their families,” said Dr. Rao. He added that because AD predominantly affects the elderly, “postponing symptoms for five years would cut the national burden of disease in half, and delaying onset for 10 years would nearly eliminate it.”

The observational findings of Dr. Rao’s team stimulated the idea of the CYCLE-AD trial, which is designed to assess the disease-modifying effects of a high-intensity exercise intervention aimed specifically at sedentary elders with the APOE ε4 variant.

Dr. Alberts is also leading a study to investigate the effects of a cycling program on patients with Parkinson’s disease. Earlier findings from his group indicated that the intervention leads to significant motor and cognitive benefits.

“Exercise appears to have a powerful effect on cognition,” said Dr. Alberts, who is also Vice Chair of Innovation in the Neurological Institute. “Our challenges are to find out how much activity makes a difference for altering the progression of Alzheimer’s disease and to devise a widely available program that’s interesting enough for people to consistently engage in during their senior years.”

Study essentials

To be eligible for CYCLE-AD, individuals must be between ages 65 and 80 years and be an APOE ε4 carrier. All subjects must be healthy, cognitively intact and sedentary at baseline.

The study will randomize 150 participants to either the cycling program or unmonitored usual activity. Subjects in the exercise arm will undergo high-intensity interval training (60-90% of heart rate reserve) three times a week (minimum 90 minutes/week) for 18 months using the Peleton® home cycling system. They will be monitored for exercise adherence and encouraged to exercise through motivational interviewing, an established and validated method for increasing participation in healthy behaviors.

Subjects will be blindly assessed at baseline and 18 months with comprehensive cognitive testing and brain structural and functional MRI. Of particular interest is the hippocampus, a brain region critical to healthy episodic memory function and one of the first regions to show changes associated with AD. Cognitive and imaging measures, along with measures of physical fitness, will be assessed at study entry and 18 months.

Thoughtful study planning

According to Dr. Alberts, the team chose the Peleton® system because it offers several motivational features compared to conventional exercise bikes, including background music, group classes with interactive capabilities and the ability to track performance gains. The system also measures program compliance and exercise parameter data (mean resistance, cadence, heart rate and total output), which can be collected and tracked remotely by the investigators.

CYCLE-AD is further distinguished by two other aspects of its study design:

  • Potential advantages of high-intensity interval training. Frequent modulation of exercise intensity is believed to combat boredom and increase exercise efficiency. Some evidence suggests it also leads to better cognitive improvement compared with a continuous exercise level.
  • Scalability to a large population. The program will be applicable to any indoor cycle, as cycling courses can be streamed online. “Once we know the appropriate level of exercise to make a difference, a similar home exercise program can be rapidly recommended to a large population,” noted Dr. Alberts. “A low-cost, effective intervention that does not involve pharmaceuticals would be most welcome to stave off Alzheimer’s disease in high-risk individuals.”

“This is also an ideal study for the COVID-19 era, as the intervention and monitoring can be done from home,” added Dr. Rao.

Article adapted from Consult QD.

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