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

The National Institutes of Health has awarded Cleveland Clinic a $6.7 million, five-year grant to evaluate the effect of high-intensity exercise — using a home-based, internet-connected indoor cycle — for preventing development of 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 Stephen Rao, PhD, staff in the Cleveland Clinic Lou Ruvo Center for Brain Health – Cleveland, and Jay Alberts, PhD, staff in the Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute.

A quest to slow AD progression

Prior to this grant, Dr. Rao’s research team conducted an 18-month observational study that found that moderately physically active carriers of the apolipoprotein E epsilon 4 (APOE ɛ4) allele, the most important known genetic risk factor for late-onset AD, experienced significantly lower declines in episodic memory and hippocampal volume compared with carriers who were sedentary. No such exercise differences were observed in noncarriers, suggesting that exercise provides a unique benefit in slowing disease progression in people at genetic risk of AD.

“Slowing progression can make a huge difference in the quality of life of patients and their families,” says Dr. Rao. He adds 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 ɛ4 allele.

Dr. Alberts is also leading a study investigating the effects of a cycling program on patients with Parkinson’s disease, as previously reported on Consult QD. 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,” says Dr. Alberts, who is also Vice Chair of Innovation in Cleveland Clinic’s 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 an APOE ɛ4 allele carrier. All subjects will 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% to 90% of heart rate reserve) three times a week (minimum 90 minutes/week) for 18 months using the Peloton® 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 at 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 at 18 months.

Thoughtful study planning

According to Dr. Alberts, the team chose the Peloton system because it offers several motivational features compared with 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,” notes 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 era, as the intervention and the monitoring can be done from home,” adds Dr. Rao.

NOTE: Drs. Alberts and Rao are inventors of technology used in this study that Cleveland Clinic licensed to Qr8 Health Inc. Cleveland Clinic, Alberts and Rao have equity interests in and rights to royalties from Qr8 and serve as consultants to the company.