NeuroVoices: Stephen Rao, PhD, and Jay Alberts, PhD, on High-Intensity Exercise in Preventing Alzheimer Disease

February 24, 2021
Marco Meglio
Marco Meglio

Marco Meglio, Associate Editor for NeurologyLive, has been with the team since October 2019. Follow him on Twitter @marcomeglio1 or email him at

SAP Partner | <b>The Cleveland Clinic Foundation</b>

The duo from Cleveland Clinic discussed their recently initiated study which will evaluate the neuroprotective features of home-based intervention in high-risk individuals for Alzheimer disease.

The National Institutes of Health (NIH) recently awarded a $6.7 million grant to Cleveland Clinic for its CYCLE-AD (Cycling to Cease or Limit the Effects of Alzheimer Disease) clinical trial, which will evaluate if high-intensity exercise can prevent development of Alzheimer disease (AD). The 5-year study will assess the effect of home-based indoor cycling using a Peloton bike in slowing disease progression among healthy older people at high genetic risk for developing the disease.

The home cycling system has interactive capabilities and has the ability to track performance gains, as well as measure program compliance and exercise parameter data. All of this data will be collected and tracked remotely by researchers, including co-principal investigators Stephen Rao, PhD, and Jay Alberts, PhD.

If successful, the study has the potential to provide a scalable intervention capable of substantially reducing healthcare costs by modifying the trajectory of the disease. Rao and Alberts sat down as part of our NeuroVoices series to provide background on the study. In the first half of our conversation, the duo explained what had been observed in terms of prevention methods and exercise, as well as the details behind a separate study Rao previously conducted.

NeurologyLive: Can you provide an overview of the study? What are you trying to observe?

Stephen Rao, PhD: We have noticed over the years through some observational studies that when we look at people who are genetically at risk for Alzheimer disease but do not have yet have any symptoms, the people who exercise are less likely to develop Alzheimer like changes than the people who do not have the genetic risk factor. That was an important discovery for us. We’ve been following that up with several types of research to try to understand how exercise can be neuroprotective. In fact, there is a large, ongoing study right now doing that. It looks at the chemical that pay the brain and how that might change. We’re looking at PET scans, MRI indexes, and cognitive dysfunction. But those are all observational studies.

We decided last year to submit a grant to the NIH to try to understand if we could actually modify it rather than just make look like an observational study. In other words, all the people we’ve studied now are people who’ve been exercising on a regular basis. The study that we’re going to do takes 150 people who have the genetic risk factor, all between the ages of 65 and 80. They don’t have any memory problems or any other changes that would attribute to Alzheimer disease, but they’re also individuals who are relatively sedentary that don’t exercise on a regular basis.

Half of those individuals will be randomized to a condition in which they get a Peloton bike into their home. When we wrote this grant, we knew that older sedentary individuals are less likely to go to gyms or a research facility. But at the time we submitted it, and by the time it was reviewed, it became obvious that this was the way to go. We had proposed something where we brought them into a lab, and that didn’t work very well, so we opted not to go that route.

This was the best way. What’s nice about the Peloton bike is that it’s interconnected through the internet, allowing us to monitor whether people are actually exercising or not.

One of the things that’s unique about this study that we’re not trying to improve people’s cognition, we’re trying to prevent Alzheimer disease. We’re monitoring over an 18-month period, looking at their cognition based on neuropsychological tests and giving them MRI. This way we can measure the changes in the rate of atrophy in a key structure of the brain called the hippocampus, which is one of the first structures to go in old timers. Our main hypothesis

But one of the things that's unique about this study is we're not trying to improve people's cognition, which kind of prevent Alzheimer's disease. We're monitoring over an 18-month period, we're looking at their cognition based on neuro psychological tests, and we're giving them MRI. We can actually measure the changes in the rate of atrophy in a key structure of the brain called the hippocampus, which is one of the first structures to go and old timers. Our main hypothesis is that the group that has Peloton bikes in their home are less likely to show Alzheimer-like changes over that year and a half than people who are genetic at risk, who are sedentary, and basically engage in the amount of activity they normally do, which isn’t a lot.

We’ll see if there are differences. The goal is that we’ll see some difference, and that we can prevent the illness. If we can delay the onset by just 5 years, we can cut the number of people with Alzheimer disease in half. If we delay it by 10 years, we can practically wipe out the disease. Prevention is sometimes the better way to go than to try to reverse the effects in someone who already has the disease.

Jay Alberts, PhD: I think what Dr. Rao mentions is spot on. We hear a lot about the concept of exercises and medicine, which has been out there for a long time, but the interesting part of our project is that we’re going to be able to give the exercise as medicine before they potentially need medicine. That is very important. We can view these things as prevention or slowing the number of people who convert to Alzheimer disease.

At the end, because we have all of this rich data from the exercise sessions, as well as the cognitive and imaging data, if successful, we should be able to provide a better prescription for individuals who might be at risk. We can talk about exercise medicine all day, but when you’re at risk or you have a neurological disease, you want to know what you should do. Hopefully, at the end of this study, we’re able to prescribe a type of exercise level of intensity, where we know that prescription is effective.

NeurologyLive: Can you detail your findings from the 18-month observational study?

Stephen Rao, PhD: Our earlier study was just with MRI and cognition, and it spanned 18 months. We gave people a simple questionnaire asking how often they exercised and then divided people into 2 groups. That study produced very interesting results and prompted us to say, ‘let’s try to figure out what mechanism is within exercise and why is it neuroprotective.’ The only way we could actually answer that question is to do more sophisticated testing. We did a lumbar puncture, examine the cerebral spinal fluid, and also use PET scans to try to identify the changes in the brain specific to Alzheimer disease like the buildup of amyloid and neurofibrillary tangles.

Our understanding is that we’re probably not going to be able to get everybody to exercise, but we may be able to understand the mechanisms by which exercise prevents Alzheimer disease and perhaps that could be used to create some type of pharmacological intervention. For example, taking a pill that replaces exercise. While I’m not sure that specifically will happen, but if we can, that would be useful for the majority of people with Alzheimer disease.

The other thing we’re doing is looking at a much wider range of exercise patterns. On 1 hand we’re looking at people who are sedentary, but we’re also looking at the person who has run triathlons. We’re also comparing the people who exercise on a more regular basis, maybe 3 times a week. These people may get on a bike or take yoga classes, something more low impact.

The question is, is there a dose response? How much exercise is really needed to be able to offer neuroprotection. Secretly, I’m hoping there is no difference between mild to moderate exercise versus a lot of exercise. Because if there’s a dose response effect, it’s unlikely to get people to become marathon runners when they’re 65. Nonetheless, we’re going to examine that question.

Transcript edited for clarity.

National Institutes of Health awards Cleveland Clinic $6.7 million grant to evaluate impact of high-intensity exercise in preventing Alzheimer disease. News release. Cleveland Clinic. January 28, 2021. Accessed February 23, 2021.