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AAIC 2022 | EXERT results: exercise shown to stall cognitive decline in patients with mild cognitive impairment

The Phase III, multicenter, randomized EXERT trial (NCT02814526) enrolled almost 300 patients to investigate the effects of regular exercise on brain function in previously sedentary older adults with mild cognitive impairment (MCI). Patients were randomized 1:1 to undertake moderate intensity aerobic training or stretching, balance, and range of motion (SBR) training for 18 months. For the first 12 month, exercise was supervised for 2 sessions per week and independent for 2 session per week. Laura Baker, PhD, Wake Forest University School of Medicine, Winston-Salem, NC, presents the topline results of the EXERT trial after 12 months. Surprisingly, neither the aerobic exercise nor the SBR arms showed decline from baseline on the ADAS-Cog-Exec at 12 months, assessed as the primary endpoint. Clinical Dementia Rating scale Sum of Boxes (CDR-SB) scores also showed no change. To try to understand these findings, the outcomes were compared to matched controls from the ADNI-1 longitudinal observation study. ADNI-1 MCI participants showed the expected 12-month decline on the ADAS-Cog-Exec. These findings suggest that both the aerobic training and SBR interventions may have prevented cognitive decline. The social support aspect of the intervention may have also contributed to the effects seen. Dr Baker shares her thoughts on these data and provides recommendations for patients with MCI. This interview took place at the Alzheimer’s Association International Conference (AAIC) 2022 in San Diego, CA.

Transcript (edited for clarity)

What I’m going to be showing or sharing at this, the AAIC meeting is a couple of different things. We have some summary points. So number one, we found that you can get people with mild cognitive impairment to stick to a 12 month intensive exercise program. And by intensive, I mean you have to work four times a week. You have to show up, you have to do this. Our final enrollment number was 296, so I’m very proud of that, it was just four short...

What I’m going to be showing or sharing at this, the AAIC meeting is a couple of different things. We have some summary points. So number one, we found that you can get people with mild cognitive impairment to stick to a 12 month intensive exercise program. And by intensive, I mean you have to work four times a week. You have to show up, you have to do this. Our final enrollment number was 296, so I’m very proud of that, it was just four short. But of our 296 people in 12 months, they completed 31,000 exercise sessions.

And I think, for me, that is a success already, no matter what, because with mild cognitive impairment, they have their challenges every single day. Getting from point A to point B is not the same as it is for people without mild cognitive impairment. So their daily challenged, and they were able to work in the exercise. So to me, that’s an important part. What I’m going to show you is that there was benefits. And the question you always say well, will they do it though? And my first point is, yes, they will do it.

So, number two, we did this trial during a pandemic. Only half of our participants had exited the study at the time as of March 2020, which in the US really hit us hard. And so we had to pause the study, but we stayed in touch with our participants. We called them every week, make sure they were still exercising. They would report, “Oh my gosh, I’m not going to stop my EXERT exercise.” So they kept exercising. And then once we restarted the study, some of the YMCA, many of the YMCAs were closed. And so we’re in the middle of the study. How are we going to keep them exercising? It’s their medicine.

So we did all kinds of things. Our trainers met them outside. We had virtual appointments. We had virtual training. We sent them to other video classes, but we still checked in with them to make sure they were still doing their four sessions per week. So this is another main message, is you can not only get them to do this, people with mild cognitive impairment, but you can get them to do this in a pandemic, during the pandemic. And, for us, this is life. We had a pandemic and when it passes, these people are going to deal with many other daily challenges in their life. It’s just part of the disease. And so, for me, to show that we have a positive signal, even during a pandemic, means it could be a sustainable finding in the context of other challenging life events. So pandemic part to me is important for generalizability.

Okay. So what did we find? So as a surprise to us, we found neither group declined over 12 months. The people with mild cognitive impairment, we went into the study expecting 12 month declines for some people. It’s the natural course of the disease. And we’re using, how we’re measuring decline, we have our global composite score that’s been validated. It’s called the ADAS-Cog-Exec. So we added executive function for the reasons I talked to you about earlier. So it’s ADAS-Cog-Exec. It’s been published. So it’s our global composite in that stretching and balance group and in the aerobic group, they both remain stable for 12 months. So we’re thinking, well, is this just because is there something, maybe these days in COVID, in these times, people don’t decline like they used to? Maybe there’s just no effect and it didn’t change at all.

So what we did is we had a comparison group, a usual care comparison group, and we used ADNI. ADNI is a Alzheimer’s Disease Neuroimaging Initiative, is an observational, longitudinal observational study. It’s like usual care. And what we did is we went to that study. We found participants who were just like EXERT participants in terms of their age, their sex, how impaired they were at baseline. So many different components of EXERT. We matched the two groups. And then we looked at these people in ADNI and said, “Do they change over 12 months on our same measure?” Yes, they all got worse. But our participants, whether participated one of those two interventions, did not.

So it makes us feel better that this it’s not that there was no effect, but it really is that either intervention was enough to slow or stop progression on average for these individuals. I think a key ingredient is all of our people were sedentary coming in. So what we see is that any change, so these people went from zero, they had no exercise, to they’re both doing regular exercise for 12 months, completing 31,000 sessions. When you start at sedentary and you add exercise to your life, regardless of what type, your cognitive decline stops. And so we’re continuing to look at other measures that we have, but so far all signals that we look at, no matter what test we’re looking at, we have other tests, we’re all seeing the same thing, that there’s no decline in these people who should have declined.

This opens the door for anybody who’s willing to increase their activity. And our amount of time, or the recommendation we’re going to put out is the amount of time our participants in both groups exercised was about 120 to 150 minutes per week. That is what our recommendation is going to be, is that for people with mild cognitive impairment who are sedentary, we are suggesting an increase of 120 to 150 minutes per week of any type of exercise, whatever’s going to work for them, whatever’s going to feel good for them, is going to be a risk reduction strategy. And so for me, the public health implications is that this is doable for everybody. If it was only aerobic, we’re going to leave out a lot of people, maybe probably 75% people are not willing to do that. But if it’s any kind of exercise, that’s possible.

And the last point I want to make is this, our intervention involved a lot of support. And so what I would want to see is the standard recommendation going out to clinicians that you need to get your folks exercising. Well, that’s great, a great idea, but we have learned, and for all my studies, this is always true, you cannot expect someone mild cognitive impairment to go exercise on his or her own. It’s not possible. And if you expect them to exercise on their own, this program will fail. It will absolutely fail. And it’s possible that it’s the support element to this that is synergistic with the exercise to give them a boost.

And I feel like it’s that message that really needs to go out there. I hear over and over from clinicians that they’re trying to get their patients to start exercising more, but in MCI, mild cognitive impairment, your ability to initiate and organize and get going on new projects, that’s what’s impaired. And so to ask someone to start exercising without support, these folks just don’t know how to do it. And if they can do it once, they can’t sustain it. And so I think that is really a critical ingredient on a new recommendation, has to be supported. Not necessarily by a trainer, but it has to be some buddy system, something where someone is with that person to help them stick to the program.