Can We Prevent Cognitive Decline in Aging? Multi-Domain Trials with Laura Baker and Ellen Binder

Eric 00:13

Welcome to the GeriPal Podcast. This is Eric Widera.

Alex

This is Alex Smith.

Eric

And Alex, we’re going to be talking about, can we prevent cognitive declining aging through multi-component interventions? Talk about what that is. Who do we have in with us to talk about? We are delighted to welcome Laura Baker, who is a cognitive neuroscience science researcher at Wake Forest University School of Medicine.

Laura

Laura, welcome to the GeriPal Podcast. Thank you. Happy to be here.

Alex

And Laura’s also first author and co-PI of one of the trials we’ll be talking about, US POINTER. We’ll have a link to that in our show notes. And we’re delighted to welcome good friend Ellen Binder, who’s a geriatrician and researcher at Washington University in St. Louis, deputy editor at the Journal of the American Geriatric Society, or JAGS, and She and I have co-led the JAGS Junior Reviewer Program for years. Ellen, welcome to the GeriPal Podcast.

Ellen 01:04

Thank you. Great to see both of you.

Eric 01:07

And Ellen is a senior author for the Risk Reduction Alzheimer’s Disease Trial, or RRAD, which we’ll also be talking about in the show notes. So we got a lot to talk about. This big question is, can we actually help improve cognitive function or at least prevent cognitive decline in older adults? As people age. But before we go into that topic, Ellen, I think you have a song request.

Ellen 01:32

Yeah. Get on Your Feet by Gloria Estefan.

Eric 01:38

I haven’t heard Gloria Estefan’s name since…

Eric 01:40

It’s been a while. Been a minute.

Eric 01:42

Grade school. Yeah. Yeah. Going to a dance in grade school. Uh, my heart is palpating. I get that anxiousness when I hear her.

Eric 01:51

And why, why this song?

Ellen 01:53

I wanted to energize people, and I’m a big proponent of exercise.

Eric 01:58

So, right. All right, here’s a little bit.

Alex 02:03

(singing)

Eric 03:03

Going all the way back to 1989. Ah, ’89. ’89. Yeah.

Eric 03:08

I believe it. That sounds right. Thank you, Ellen.

Eric 03:11

Wonderful song. All right, let’s, let’s dive into the topic at hand. I gotta say, medicine in general, myself included, I am so used to looking at like single intervention trials. Like, does this drug do X? Or even in this regard, does exercise decrease falls or improve cognitive function? We’re going to be talking about multi-domain studies, multi-targeted studies.

Why the focus on this rather than just continuing to do kind of single intervention studies around exercise or diet? Like there was a big study in New England Journal just a couple of years ago on the MIND diet. Yeah. I think that one showed no benefit from the MIND diet versus usual control after 3 years. Laura, I’m going to turn to you. What’s your take on this?

Laura 04:01

We are in a different place in science in 2025, 2026 is where we are now than we were 20 years ago, 30 years ago, 40 years ago. I think we initially started to consider the treatment of Alzheimer’s problem as a, you know, a very focused unidimensional, let’s find the one drug that can treat the disease. And, but since that time, after multiple failures in our drug trials, we have kind of moved towards, you know, what’s the special cocktail that’s been so successful in cancer and HIV?

What, why are we dragging our feet in Alzheimer’s disease? So I think there’s just, we’ve, as a community, we’ve moved to more towards combination trials. We studied combination of lifestyle behaviors, but there’s so many other trials now in the making that can combine different medications and also lifestyle plus the medication. So we’re just in a different era. We are trying a different approach and that, that target, that, that multi-domain combination is more likely to hit multiple targets.

It’s more, it can be personalized to an individual and the specific health problems for an individual. Whereas a single target cannot. So I think it’s just, it’s a reflection of the times of where we are in science.

Eric 05:26

And do you, is it because like a single target only can do a little bit of thing and adding another one is additive, or is it that you really need the combination of them? Like it’s really synergistic. You need diet and exercise and good vascular modification to actually hit that, you know, golden ticket for Alzheimer’s prevention or dementia prevention.

Laura 05:48

So I’ll just say, I’ll just say one thing and that is, and then I’m going to pass it. But I think we thought that we made the mistake of thinking Alzheimer’s disease is a simple disease with a simple solution. And I think I’ll pass the baton at that.

Ellen 06:04

I was only, I was going to say that we, we have learned, Blake, from fall interventions that multi-component interventions have been more effective because they’re able to target more risk factors. That’s kind of the hypothesis for a lot of the trials, such as POINTER and FINGER, that are trying to address the multiple risk factors for Alzheimer’s disease that we know exist.

I don’t know yet whether we can pinpoint yet, you know, which components are much most effective or, you know, but it’s appearing that just as Laura said, having more components at this early stage of this research seems to have more effect.

Eric 06:56

Spoken like a true geriatrician, Ellen. The answer is always multi-component for any geriatrics test. And then in general, like even when I think about single intervention trials like Sprint Mind, we did a podcast on SPRINT. With Jeff Williamson. Jeff Williamson. The primary outcome there was negative.

Eric 07:15

It was a combination of MCI and dementia. But when you just looked at MCI, there was some improvement versus dementia. So there is some evidence, right, for single intervention trials, but it’s kind of mixed is my guess, my gathering of the data. Does that sound right?

Ellen 07:33

Well, ARAD was kind of modeled after SPRINT. in many ways. And, you know, that study was targeting individuals with hypertension that wasn’t at the more aggressive targets. It did not show efficacy for the cognitive outcomes that we prespecified.

Eric 07:55

Yeah.

Ellen 07:56

But I do want to point out, for almost all these trials, that everybody got better. It isn’t that we saw cognitive decline or less decline.

Eric 08:09

Well, let’s, we’re going to hold on to that. Like, why is everybody getting better in these trials? But let’s actually talk about the trials first. So I’m going to go back all the way over a decade ago, 2015. I remember the FINGER trial came out. Laura, would you mind just describing what the FINGER trial was and how you think about it?

Laura 08:31

Sure. The FINGER trial is, it’s an acronym that includes Finland and geriatrics. That’s kind of how they got to FINGER. But it was a study. It was just quite revolutionary in its time that we’re going to, they’re going to test, you know, whether you can change behavior. I mean, change behavior and change risk. I mean, who would believe that?

Eric 08:58

And change behavior in older adults, not like a 6-year-old.

Laura 09:01

Yeah. And in older adults who were not doing these behaviors, these are new behaviors, new habits for these individuals. So they, so that was the idea. It’s kind of going to improve the, you know, move folks toward a healthier lifestyle. And let’s see what happens. And they, uh, they picked people who were at risk. It’s over about 1,200 people, all at risk for decline. That’s key. If you’ve got a bunch of really healthy folks and you’re putting them into a behavior change and they’re already doing these behaviors, there’s no room for improvement.

So the selection of the people is really important. So they found the right people. They, uh, they had the right program that in terms of, you know, they chose 4 domains. So move more, eat a more colorful plate. There’s a very specific diet, then more of a Nordic diet, which is very Mediterranean. Um, and then, uh, stay intellectually engaged, challenged, get out of your comfort zone, stay socially connected, and know your numbers. You know, what’s going on under the hood. Uh, so what’s your blood pressure?

And, and they, so they met with the medical personnel. And so another key ingredient about FINGER is they didn’t expect changes over 6 months. It was a 2-year trial. I mean, in order to change habits, change, you know, the health of the body and therefore the health of the brain takes time. Yeah. And So that’s why a lot of these, you know, studies that, you know, mixed results, oftentimes they’re too short. They’re not enough time to make a big change. So Fingerman had 1,200 people, at-risk individuals. There was a, the control was a health education versus, you know, a lot of support to help change behavior.

What they showed was that cognition improved, global cognition, but also memory and executive function changed. and processing speed improved over a 2-year period in these people who were in the more, in the, in the multi-domain behavioral change intervention. And the other cool thing about their study is that not only did they just look at the 2 years and then stop, they’ve been following these people over time and they’re continuing to follow them now.

So that’s just really so often in our NIH structure, we follow people for 5 years and we never see them again. This is different in FINGER, and it will help us know what the legacy of that exposure will be over time. And I think they’re in their 11th year of follow-up right now. But these people had lower comorbidities. They had higher ability to carry out their daily function. It’s not just cognition. It affected other aspects of their life.

Eric 11:33

Are they continuing to do the intervention? Like, is the adherence still there for 11 years later?

Laura 11:40

Some, I mean, there’s, you know, there’s not, there’s not a rigorous monitoring. There’s the questionnaires. And of course, you know, humans, when we answer a questionnaire, we’re always doing more than we actually are doing. So there’s that. But, but there’s, I think that they’re really focused on what’s the legacy of that exposure.

Eric 11:56

Yeah.

Eric 11:57

Ellen, what’d you think when you first saw FINGER?

Ellen 12:00

I mean, I think it’s impressive. I don’t have as much in-depth knowledge about it as Laura, and I’m kind of curious Like, I am not sure what interventions were most commonly implemented. I didn’t see a lot of detail about that. Do we have any sense of what aspect of it? Okay.

Laura 12:25

Oh, oh yeah.

Ellen 12:26

More about

Laura 12:26

that. So Mia Kivapeltto is also an investigator on POINTER. So our whole model was, let’s not, let’s not start at chapter 1. Let’s start at chapter 2 and let’s use lessons learned from FINGER. So I love that model. You include the people who did the previous study on your study so that you know that you could carry the torch forward.

So, so Mia advised us all along that worked, that didn’t work, that worked, that didn’t work. So a lot of our protocols were developed with those lessons learned. So in the FINGER trial, they had supervised exercise, um, at, in a, in a group setting, uh, 3 times a week for the whole 2 years. It was pretty intense. And these were by, you know, physiotherapists. So in Finland, these are exercise physiologists basically. And, and, uh, diet was, uh, it’s a, it was a basically the MIND diet, but more focused on fish. So it’s a Nordic diet. Um, so, uh, it’s a lot of fish in the area, whole grains, you know, those kinds of things.

So very similar to the MIND diet. Uh, they had a computer training program. It didn’t work. They didn’t, the participants didn’t like it. So Mia says, don’t use that one, go to something else. And so we did. Um, but that was, that was the primary intellectual challenge. We added more in POINTER and the social engagement. They had the exercise session and they did meet with their, you know, facilitators. And then they met with, uh, uh, medical personnel, um, every couple of months just to kind of review and that.

We learned that the white coat phenomenon in Finland had a huge effect on adherence to the intervention. So because of their experience, we added that to ours. Uh, so it’s truly a multi-domain intervention.

Eric 14:11

So, and pretty intensive.

Laura 14:13

Yeah.

Eric 14:13

Yeah. Pretty intensive.

Ellen 14:15

Everybody did everything, right?

Laura 14:17

They did. It was a full, it was a full, all 4 components were made up of one intervention. We’d never thought of it. They didn’t and we didn’t. It’s not 4 interventions. There’s one.

Ellen 14:27

So when you say it didn’t work with the cognitive training, is it that people like said, I just don’t want to do this anymore, or—

Laura 14:36

They were bored.

Ellen 14:37

Okay. Oh, wow. And it’s not a fun cognitive activity. The cognitive training protocol was a game. What, what was it?

Laura 14:49

So it’s a, it’s a computer cognitive training. It was developed for cognitive training, for exercise. cognitive exercise.

Ellen 14:57

Yeah. Yeah. Okay.

Laura 15:00

Yeah. So since then, you know, Posit Science here in the U.S. with their BrainHQ published with the ACTIVE trial. So BrainHQ got a lot more visibility in this country. Yeah. So that’s what we went to, but what they were using, I mean, they started their trial back in late 2000s. We just didn’t have the same So they had to go with the best that was available. And when I say it doesn’t work, they still had people who did the study, but did that particular component, but it was just hard for them to stick with it. It was just hard.

Eric 15:32

So let me ask you this, Laura. So positive trial showed a difference.

Eric 15:37

We’re done.

Eric 15:37

We’re done.

Eric 15:39

Why, why do anything more? Like why replicate it in the US? You have to switch out the cod for something else, but what, what was, what, what questions were left at the end of that?

Laura 15:50

Have you been to Finland?

Eric 15:52

No, no, I haven’t.

Laura 15:54

You should go to Finland.

Eric 15:55

Yeah.

Laura 15:56

Tell us about Finland. It is a different place.

Eric 15:58

Yeah.

Laura 15:59

People ride their bikes everywhere. They have socialized medicine. Everybody uses their doctor every year. You always have your blood tests. The diet is very different than our takeout diet in the United States. We are very different people. We live our lives very differently. So it works in Finland. That’s fantastic. Is it going to work in America?

We have way more comorbidities in terms of cardiovascular disease. We, we sit way more. We walk much less. We eat processed food. We use pesticides a lot more. We, we, we have urban sprawl with low socializations. We don’t talk to each other. Now, post-COVID, you know, that adds a whole nother layer, but we are different people. And just because it works in one population. Because it’s a behavioral intervention, you’re hopeful that it’s going to work in the U.S., but there is zero guarantee that it will.

Eric 16:54

So you decided—

Ellen 16:54

It’s amazing it worked in such a healthy population that they were able to show that the difference that they did.

Laura 17:00

Remember, they were all at risk though, Ellen. They, they used the CADE score for midlife risk and they were all at risk. So they, they excluded a lot of really healthy people, but they included those who are at greater risk. Yeah, that’s a key. That’s a key.

Eric 17:15

So let’s talk about US Pointer. You also focused on people at risk. Who are the people at risk that you focused on aside from every American is close to being at risk?

Laura 17:27

Uh, you’re not too far off in that comment right there. That actually, it’s a small proportion, uh, relatively small proportion that are not at risk due to lifestyle factors. We just do not have a healthy culture in general. Um, you may know lots of healthy people, but that is a subset. Um, so we, what, what we wanted to do is just try to capture the typical American population. So we had 5 sites across the United States that was intentional to get the Californians are very different than those people who live in North Carolina, who are very different than those people who live in Texas.

And so it was really important for us that we get microcultures, uh, all included, not just for health status, but If it’s a behavioral intervention, we need to listen to them. What’s going on in that part of the country? Is it cold? Is it hot? What kind of foods are your comfort foods? We need to listen to them so we can continue to adapt the interventions and meet the needs of people no matter what their culture is. So that was really important. So we had 5 group, 5 sites, 2,000 people. Our inclusion where you had to have risk. We have 2 years to watch people. If they’re not at risk, we’re not going to see decline in 2 years. Maybe if we have 20 years, we’ll see it. So I had 2 years of risk.

So everybody’s at risk and they could be at risk for, we’re all at risk for different reasons, but our risk where you had to be a certain age, age is a risk. Uh, you had to be 60 to 79. We’re trying to mimic FINGER a little bit. You had to be sedentary. So not a regular exerciser. That was key. That was our primary exclusion. All of the exercisers wanted to get into the study. Uh, yeah. Uh, you had to have not be already eating a healthy diet. So not already eating a Mediterranean diet. That was an easy inclusion area. We had very few people excluded because they were eating too healthy of a diet, Americans. This is what we want.

And then we had, then you could get risk scores from multiple other things like your race, ethnicity. We have certain groups, subgroups that are at higher risk. If you’re older, over 70, you’ve got a risk point. If you had any mild, at least mild cardiovascular disease, so mild hypertension, mild elevated glucose, mild elevated cholesterol, any one of those, mild elevated blood pressure, you got in, but you had to have risk to get in.

Eric 19:41

So let me ask you this. When you’re designing a trial like this, how much of it is, A, we want to make sure that the intervention does something. So if people are already doing it, we’re not going to be able to show a change. And how much of it is we actually just need it to show a change within 2 years.

Eric 19:58

So it’s not necessarily We don’t think this is appropriate for a healthy 30-year-old to do this. It would just take a lot more years and a lot bigger trial than focusing on those highest-risk patients.

Laura 20:12

Oh, we know, I mean, Ellen can tell you about it. We know exercise is good for everybody. I mean, this has been shown in all populations across the lifespan. There’s so many benefits, but our focus is protection of brain health. protection of cognition. And so we had to pick the people that we can see protection within a short period of time. So we’re now into another phase, rolling it out into the community. And the question we get asked all the time is, can we enroll younger people, older people? And we’re going, yes, of course. Of course. It was for a trial. So that was a focused intent there.

Eric 20:48

I have a question on the other end of the spectrum. Many of our listeners care for very older adults, you know, geriatricians, patients who are in their 80s, 90s, et cetera. Was there an age cap on POINTER?

Laura 21:03

Yeah, 79, just because it was, we were trying to mimic, we want to be able to relate our findings to the finger findings.

Eric 21:09

To the finger findings. And do we have any evidence about, you know, multi-domain intervention trials directed at cognition in people over the age of 80?

Laura 21:22

Ellen?

Ellen 21:23

I’m not aware.

Eric 21:26

Not off the top of your heads?

Ellen 21:28

I think the challenge, and the challenge with all these trials, is that that is when dementia starts to emerge in much greater numbers, and sorting that out is challenging, even in these trials. So there’s some benefit to that, in fact, because that’s someone who’s at really higher risk. But I think there’s just a little bit more research challenges. I, I, there are trials looking at patients with MCI and early AD, and I don’t know specifically what the age range was for that.

Eric 22:05

Yeah. I mean, speaking anecdotally, you know, care for patients with cancer and they get a diagnosis of cancer and suddenly they stop smoking, they start eating differently. Similar sorts of things. Somebody gets this diagnosis of mild cognitive impairment or early-stage dementia, right? And suddenly they start moving around a lot more and maybe change their diet in hopes of forestalling things. But we don’t actually have any evidence that when you’re 87 years old and you institute those interventions, it might be helpful. We think it’s probably true, right? But I don’t know.

Laura 22:36

Yeah.

Eric 22:36

Or do we have, can we extrapolate and say, sure, I’m sure it helps. It works well in 79… there’s no 70-year-olds,

Ellen 22:43

or why not in 89-year-olds? Well, I think the other message is that for these interventions, there are many health benefits, right? I mean, we’re focusing on cognition and dementia, but there are benefits for physical function.

Eric 23:03

Fall prevention.

Ellen 23:04

Probably, you know, depending on the intervention or the component, for cardiovascular health. that are very important. And so I think the message is that just because you are getting older, it doesn’t mean you shouldn’t do these things, right? Yeah. It’s a, it’s a lifetime lifestyle, and we’re trying to pick the age, the risk factors to target the population that we can demonstrate benefit. Yes, we can’t directly Apply to everybody else, but it’s certainly compelling.

Eric 23:41

Laura, what were the interventions that you focused on? Were they similar to Finger?

Laura 23:46

They were, and they, I would say they were more intense. Uh, we, and it’s not always intense in terms of, you know, how hard people have to work. I think we use the word intense maybe incorrectly a lot. There’s many, many dimensions to the word. It was more intense in terms of the accountability.

Eric 24:04

Uh-huh.

Laura 24:04

And the support. So more support, more accountability. And, and in terms of, uh, you know, I, I, my, my world is all about behavior change. And so when you, I’m gonna ask the two of you, when you want, you want to form a new habit, it is very difficult to do that by yourself.

Eric 24:25

Yeah. Yeah.

Laura 24:26

And the, the more durable habits are formed when you have lots of support and there’s a structure in place to hold you accountable. And if either one of those are missing, the new habit just doesn’t form. And so that’s what our intensity was. And in our higher intense group was more structure, more accountability, peer support. And so the participants over time, they just got, they, they got it.

They loved it. And these are people that go, I don’t know if I can do any of this stuff. You know, I never exercised in my life. I love my food the way I like my food. I, I’m not a social person and I have no idea what my blood pressure is. These are the people that we recruited and, you know, about, about 4 months into it, they just, they loved it.

Eric 25:14

So it wasn’t hard to get them to stick to this for 2 years?

Ellen 25:18

Well, we should describe to that, to everybody. I was very impressed by the number of visits that participants had with pharmacists. And I think that’s important from a health system perspective. So I think you should just talk a little bit about that to people.

Laura 25:37

Okay. So I’m not going to count the clinic visits because I think we, the RAD, we had the same number of clinic visits every 6 months, baseline every 6 months. They come to the clinic. That’s That’s, and that’s pretty typical on a 2-year for any clinical trial. Uh, we got to do it that often in case people drop out, because if they drop out, then you have a long period of time where you have no data. So, so I’m not going to talk about that. So the other, the intervention meetings for the structured group, which is the group that got the structured program of exercise, diet, social and cognitive engagement, and, um, Health monitoring.

That structured group, they had 38 meetings over 2 years with their peers who were randomized to the same group and with a content specialist, like an exercise physiologist, nutritionist, or a health educator, plus a navigator, which is really more like a counselor-like trained person, social worker, like good with people, keeping people engaged, motivational interviewing, keep people talking. Um, that kind of behavior change kind of specialty. 38 meetings over 2 years. They were kind of stacked heavy on the first 4 months. And it’s, it’s really for the peer. It’s the peer support. Yeah. And they, they, what was interesting, we did not predict this. Between meetings, they would go see each other.

They would meet outside the meetings. When the study’s over, we’re still following these people for another 4 years. We have these community events every month for people, for our participants, and they come too and they see old friends. They go out to lunch together. They go on walks together. They’re on chat groups saying, you know, I’m having a Mind Diet meal at my house. Who wants to come? They are continuing and we’re not involved anymore. So I think that tells us that social connection with a facilitator to help them stay connected. It works.

Eric 27:37

And then real quickly, so the aspects that you covered, diet, exercise, cognitive stimulation, social engagement, social engagement, and vascular risk factors, which was diabetes, cholesterol, and blood pressure, right?

Laura 27:52

Yep. And diet, what diet did you use? Fine diet. So Mediterranean dash. So it’s a Mediterranean with low salt.

Eric 28:01

Did it work?

Laura 28:02

So our results were, I mean, I’m just like thrilled to announce that we had a positive trial. And, uh, so our, we did find that, uh, the structure, the 2 interventions, first of all, both, as Ellen mentioned earlier, oftentimes in these trials where you’re changing behavior, it works for everybody. Both groups got better in cognition. And think about this. First of all, this is way more than they get in typical standard of care.

Eric 28:28

Yeah.

Laura 28:28

They’re getting the self-guided group, you know, they get to pick their own changes and develop their own goals and kind of manage their own progress. They had 6 meetings, but who among us has had 6 meetings with other peers over a 2-year period to help you identify what your goals are? None of us have had that. So I, so it was still better than standard of care. Both groups improved, but the structured group had a significantly added benefit over the self-guided group on global cognition.

Eric 29:00

And how big of a benefit was it over 2 years?

Laura 29:03

Well, I wanted to talk to Ellen about this because I’m looking at her primary outcome and our primary outcome and just kind of like, what’s the difference between our studies? And, you know, we used a, um, you know, different choices you have when you do these kinds of trials. So if you do a trial with people with Alzheimer’s disease or dementia, you use one kind of metric, you know, and maybe it’s a general dementia screening or a dementia assessment metric. When you’re using, when you have people with mild cognitive impairment, you use a different metric because otherwise those people would be at ceiling using the dementia metric.

Now here, Ellen’s group and our group, they’re cognitively normal. They’re at risk, but cognitively normal. If we use the MCI metric or the dementia metric, They’re on the ceiling. They’re, it’s too easy for them. So we have to use a sensitive tool. That’s right. So it’s not one instrument. We used a combination of several tests that we combined together to create one composite. So people always know, well, what, what would be my score if I did, you know, did your structure? I just look at them like, uh, I can’t, I can’t really relate our score to, you know, I can’t really tell you exactly what we did. We’re able to say after doing some modeling about What do other groups do? How do they change on our test?

The best we can do right now is the cognitive benefit for the structured group. It’s as if we stalled the cognitive aging clock by 1 to 2 years. Oh. I don’t know about you. People say, well, that seems like such a small amount, but you ask our participants, would you like to slow that cognitive aging clock by 1 to 2 years? We have not had a single person say, Uh-uh. No. And people say, well, you’re asking them to do so much. It’s so much work for 1 to 2 years. But what they miss when they say something like that is all the other.. Ellen alluded to this a little bit… all the other benefits you get. I have new friends.

I feel better. I can go to my grandson’s soccer game and not trip on the grass now. I’m not falling. I can get out of the tub. I’m just, I feel proud of myself, whether or not I had any cognitive benefit. Yeah. I did this. And in an era where we have ageism and older people are just pushed to the side left and right, how to empower our older adults and give them back their voice. It’s, it’s a huge benefit to these people. So yes, it was a lot of work, but it changed them. And so was it worth 1 to 2 years of slowing the cognitive aging clock? I’ll let others decide that.

Eric 31:40

So Ellen, I got a question for you. So you just published.

Eric 31:43

Along with your other authors, the Risk Reduction Alzheimer’s Disease Study, RRAD, targeting exercise plus intensive blood pressure control, kind of a different study. Real quickly, kind of what did you do in your study?

Ellen 31:58

So this was targeting individuals with vascular risk factors, hypertension, hyperlipidemia, who were either had a family history of Alzheimer’s disease or dementia or self-reported memory complaints. And it was looking at whether more intensive blood pressure management, à la the SPRINT protocol, basically getting their blood pressure into the below 130, plus a high-intensity statin.

Eric 32:36

Yeah.

Ellen 32:37

Uh, that was the medication protocol. This was a, this were 4 groups. So intensive medication plus exercise versus exercise alone versus intensive medication alone versus a control group that, uh, Laura mentioned, uh, you know, everybody wants to exercise, so We offered a control group that had low-intensity exercise. It’s very hard to recruit people to exercise studies and then tell them they can’t exercise.

Eric 33:12

Good point. Yeah.

Ellen 33:13

That is one of the challenges also of interpreting our findings.

Eric 33:18

So what did you find?

Ellen 33:20

Well, as I mentioned, we found that, uh, participants who received both of the interventions, because we analyzed it by either exercise or intensive medication intervention had improvement, but there were not statistically significant differences between the groups, or the interaction was not significant. So would be considered a negative trial.

Eric 33:45

Yeah.

Ellen 33:46

But I think there’s some caveats. And what are those? That people got better, and we expect cognition to decline. Or just to not change, right? They get better.

Eric 33:57

Well, let me ask you that. Do, because,

Ellen 34:00

yeah,

Eric 34:01

every trial, I mean, there’s a, there’s now a lot of trials and we’re seeing cognition improve in these control or active treatment arms. I think yours, Laura, was more of an active treatment arm. They were still getting, they’re getting stuff in your, in the US POINTER study. Um, Ellen, they were getting a little bit of stuff in yours. But how much of it is just like you’re practicing these tests? You’re getting kind of less anxious when you go to the doctor to do these tests because you’ve done it before. Like how much of it is just being in these studies or the Hawthorne effect, just being studied? Like you’re, you’re going to do better over the 2 years.

Ellen 34:36

I’m sure there’s a, there’s, there’s some effect of that. I mean, there, there’s, I think Laura may be familiar. There’s more, there’s data looking at the practice effect of these cognitive tests. And I don’t think it’s huge, right? And we space it out enough that it isn’t that they’re doing them every, you know, 3 months. They’re, they’re long intervals before, between cognitive testing, 6 months.

Laura 35:03

Can I add something to what Ellen just said? Because I, I, as you’re speaking, Ellen, I just, um, relates to something else that I, is so consistent with what you’re showing. So I ran another just exercise trial. So Ellen’s had, you know, the cardiovascular treatment as well. Our exercise trial did not. It was called EXERT, and it was in people with mild cognitive impairment. And it was a 12-month exercise trial, very similar to Ellen’s in terms of the supervision.

We watched them, we gave them a lot of support, but these are people with MCI. And they had a low stretching balance group was our control versus a higher intensity aerobic. So very similar to Ellen’s. Both of our groups, our people have MCI. They should have declined over a month, over a year, and they didn’t.

Eric 35:52

Yeah.

Laura 35:52

So how do we know? So your question, you know, is this just, you know, a healthy participant clinical trial? So what we did is we matched the, all the, the, the characteristics of our EXERT people to another study, the ADNI, Alzheimer’s Disease Neuroimaging Initiative, the ADNI study, and we matched them on race, age, cardiovascular condition, everything, everything we can think we can. And they had the same test that we did in EXERT.

We looked at what happened over 12 months in the ADNI matched sample versus EXERT. ADNI folks declined significantly. EXERT people did not. Neither group. So our take-home message, similar to what Ellen is saying, is any exercise that is regularly conducted has benefits for protecting against cognitive loss over time. And we only know that because of the ADNI comparison.

Eric 36:45

That’s powerful. Yeah. Um, Ellen, other thoughts about why your study was a negative study in, uh, in the sense that you didn’t see a difference? Uh, you said there were caveats. Any other?

Ellen 36:59

Well, it, we may not have had, the other thing is that There’s been more attention to blood pressure management. We may not have had sufficient differential in mean blood pressures for that to, I mean, that’s one of the, that’s one of the interventions we were targeting, and we may not have had enough difference between the 2 groups. Mm-hmm. We also didn’t get, I mean, this was an aerobic training protocol. We didn’t get as much of a, an aerobic bump as, uh, we’d hoped. We, like many trials, had to do this during COVID And, uh, we were doing this in, in Ys and, and gyms, and they couldn’t go to the gym and they had to do it on their own. And so, you know, that, that made it a little…

Eric 37:49

I’m gonna go to my first question is, was it just not enough components? We’re talking about multi-component, multi-domain interventions. It didn’t include diet. It didn’t include cognitive training, cognitive training, social, social aspects.

Ellen 38:06

Yeah. I think those are good questions. The other one we’re not talking about that I talk about with patients that I want everybody to start thinking about is alcohol intake.

Eric 38:16

Yeah.

Ellen 38:17

You, that’s, that hasn’t been part of any of the interventions, but I do think we need to start thinking about that.

Eric 38:25

Well, we also had Christine Yaffe on our podcast a couple of years ago to talk about the SMART trial, which we’ll have a link to, but that one was personalized risk reduction. So they met with healthcare providers, staff, like nurses, and they picked— patients picked 2 or 3 modifiable risk factors. I think hearing was even one of them, which again is another one of those that could potentially be more synergistic or additive.

Ellen 38:48

Yeah. And I, I think the personalized approach, which I think pointer integrated as well, right? People focused on what was important to them is very important and important for health providers to engage with.

Eric 39:07

I have a question. It seems like with finger, between finger and pointer, we have really good evidence of the positive impact of these multi-component interventions. in not just forestalling cognitive decline, but actually improving cognitive function, which is great, or delaying, you know, for 1 or 2 years cognitive aging.

Alex 39:26

That’s great. And we have some evidence about what doesn’t work as well and some lessons learned as well from the RRAD study. Are we at a place now where we should have health system change to support these? Like, do you have a sense of what these interventions would cost or how we scale these?

Eric 39:46

Or is more research necessary?

Alex 39:48

Right. Like, why do we need more research or can’t we just do this now?

Eric 39:52

What’s your take, Laura?

Laura 39:54

No more research necessary for this multi-domain. Here, here’s why. So it’s not just those 2. It’s not just finger and US pointer. So this past AAIC meeting in London, the Latin America finger trial reported out another 1,000 people showed even stronger results than US pointer. And this is in a highly diverse population, uh, with diverse in terms of education, socioeconomic status, race, ethnicity. It works. And, you know, that was the big question for, okay, it works in the U.S. and Finland, but what if it’s really diverse and low, you know, lower income, no access to resources? It’s going to work for these? Yes.

The answer is yes, it works. So people ask all the time, I’d like to do this little study in this multi-domain thing in my community. Can you help me get started? And I say, absolutely not. We need to take it to the next level. It’s, it’s not, we, we’ve spent millions of dollars on this. We’ve done it very, very well. Um, we were very careful and we ran it through COVID too. And we, I, I, I count my blessings. I call that a gift. It helped us figure out how to deal with very hard challenges and still get people to make change anyway. So I feel like the next step is to move this out into implementation.

And I have to say, that’s what’s happening. So the Alzheimer’s Association has funded like 13 different planning grants to figure out in their own health system across the US, different teams across the US, how do you push this out? And what does this mean? Is there a pointer light? Is there a full-on pointer? Who’s going to do what? What resources do we use? So that is already starting. So I feel like we’ve got something. What do we do? More research and then wait, what, another 10 years when we have 3 large studies that said it works?

Yeah. Well, what are we waiting for? And this was the this has been the standard recommendation without scientific evidence for years. You know, you need to move more, eat better. You know, you’re too, you’re staying alone, isolated too much. And we, please come in and get your blood labs checked every more often. We’ve been saying that to our patients for years. So why would we wait and do more research?

Eric 42:08

Do you agree with that, Ellen?

Ellen 42:10

Absolutely. And as I mentioned before, there are implications for other health outcomes that are very important. I mean, yeah, all these interventions are, are, are applicable to cardiovascular and, and disability outcomes. And so, and we, you know, many of the Medicare programs now support a gym membership. That’s a big barrier for some people, but you’ve got that. Yeah. So I think, uh, it’s really figuring out the health system implementation with things like health advocates.

Eric 42:48

Yeah.

Ellen 42:48

Which will assist clinicians with a variety of health issues. You know, this is gonna spill over to what already involves diet, but yeah, medications and adherence issues. So I, I think it’s a great start and can Could have a really bigger impact.

Eric 43:11

Yeah. It’s a good reminder that we should all get off our feet, get up and make it happen.

Ellen 43:18

Get on our feet.

Eric 43:20

Get on our feet.

Alex 43:21

Wait, before, before we go to the song, can I ask a last question? Many of our listeners are, most of our listeners are clinicians who care for older adults or people with serious illness. What advice do you have to our clinicians who are You know, not able to do the population-level thing, but are caring for one patient at a time, in terms of the implications of these studies? Any thoughts?

Ellen 43:45

Tell your patients to get on their feet. Work with them at whatever level they’re willing to do. Make it applicable to their goals and make small changes. I mean, in Physical activity, in diet, in getting more socially and cognitively engaged. Small steps, goal setting. They can do that. And do what you can to help them.

Eric 44:17

Great. Laura, anything else?

Laura 44:20

I would just say to add to what Ellen said, that as a clinician sitting in a room with a patient, take just, I know we have so little time with them. Uh, that, that’s billable, but just taking a few more minutes to, uh, to figure out what kind of support that patient might have, have available to them to help them do this work. So is there a friend? Do you go to a Y? Find a trainer.

Eric 44:45

Community.

Laura 44:46

If they can’t do it on their own, they have to have support and it’s our responsibility to help them get, get that support and otherwise It’s not going to work.

Eric 44:56

I love that. Well, with that, let’s give Alex.. is going to do a little support, get us all up off our feet.

Alex 45:05

(singing)

Eric 46:05

Laura, Ellen, thank you for being on this podcast. That was wonderful.

Ellen 46:09

Pleasure.

Laura 46:10

It was a joy.

Eric 46:11

And thank you to all of our listeners for your continued support.

This episode is not CME eligible.

For more info on the CME credit, go to https://geripal.org/cme/