What We Have Learned from the Wisconsin Registry for Alzheimer’s Prevention Study

Our guest is Dr. Sterling Johnson, associate director of the Wisconsin Alzheimer’s Disease Research Center and principal investigator of the Wisconsin Registry for Alzheimer's Prevention (WRAP) study at the University of Wisconsin-Madison. The WRAP study is one of the largest and longest-running observational studies of Alzheimer's disease in the world. Dr. Johnson shares study findings, discusses advancements in brain imaging, and introduces the concept of amyloid chronicity. Guest: Sterling Johnson, PhD, professor of medicine (geriatrics), University of Wisconsin School of Medicine and Public Health

Show Notes:

  • What is the WRAP study? 3:28
  • Findings from the study: 8:06
  • WRAP studies outside of Wisconsin: 10:59
  • What is amyloid chronicity? 15:19


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Nathaniel Chin: My guest today on Dementia Matters is Dr. Sterling Johnson, the Gene R. Finley Professor of Geriatrics and Dementia at the University of Wisconsin School of Medicine and Public Health and the associate director of the Wisconsin Alzheimer's Disease Research Center. Dr. Johnson is a world-renowned brain imaging researcher. He is particularly interested in the early stages of Alzheimer's disease before people experience symptoms, and he studies this pre-symptomatic stage using biomarkers obtained through brain imaging and cerebral spinal fluid collection. Since 2014 Dr. Johnson has led the WRAP study, or the Wisconsin Registry for Alzheimer's Prevention, which has the distinction of being the world's largest family history study of Alzheimer's disease. Dr. Johnson, I'm very excited to talk with you today. Welcome to Dementia Matters.

Sterling Johnson: Thank you, Dr. Chin. It's great to be here.

Nathaniel Chin: You've been studying Alzheimer's disease for nearly 20 years. What got you interested in this field and what about it keeps you engaged in this work?

Sterling Johnson: I came to this field as a neuropsychologist, and I began studying dementia and the various pre-dementia syndromes as a young of neuropsychology trainee, trying to understand how this disease is diagnosed from a cognitive standpoint and how we can improve upon what we were doing at the time. And so that got me further and further into it from a research perspective. We started taking cognition into the MRI scanner and doing cognitive tasks with people while we were scanning their brains and watching blood flow change to the areas of the brain that were functionally involved in the task. And that was interesting and exciting and it helped us understand a lot about how the brain is organized. But we needed to do more, and so the research keeps progressing. And these days, as you mentioned, we are focused on more sensitive imaging techniques where we can still watch somebody's brain do work during the scan, but that doesn't necessarily tell us if they have Alzheimer's or are at risk for Alzheimer's. So the work we're doing now is very much about what kind of specific brain imaging techniques can we use to understand when this disease starts.

Nathaniel Chin: And it's so important that we understand the disease, how it develops, how it progresses, if we're really trying to figure out ways of preventing it and or curing it.

Sterling Johnson: That's exactly right. Yeah. We need to know how early it starts, how fast it's changing in the brain, and how it results in eventual symptoms. So these are the things we need to, we need to know in order to understand if a potential prevention drug is going to work. You need to know how fast the disease is progressing in the first place so that we would know if we're slowing it down with the right prevention strategy.

Nathaniel Chin: Now you've been a part of the Alzheimer's disease research program at Wisconsin since its inception in 2002, and in 2014 you took on the leadership role with the WRAP [Wisconsin Registry for Alzheimer's Prevention] study. So if you could give our listeners a short history of WRAP in particular, why was it created, who is in the study, and how has the study and its purpose really evolved over the past few years.

Sterling Johnson: Sure. WRAP is a fantastic study. I keep learning new things about the study every day, and I'm always inspired by our participants. So we have almost 1600 participants now, 1590, and these are people for the most part who have a parent with Alzheimer's disease. And we also have people who don't have a parent with AD, but by and large, the unifying theme for the study has been this family history component. And it's not family history of the early onset type of AD, we're talking about it's family history of the general form, the more common form of Alzheimer's disease, which is the sporadic form that develops usually after age 65. So WRAP began in 2001 by my colleague Mark Sager, and Dr. Sager was I think a visionary geriatrician here at UW. And I had the fortune of working with him from 2002 when I got here to UW and worked with him and Dr. [Sanjay] Asthana in developing the center, but also I became very involved in the WRAP study. I wrote my first grant around the WRAP study here at UW and have been writing and getting grants on this study ever since. So, it's a study about the early time course of Alzheimer's disease. Now when you think of Alzheimer's, we know from the statistics that about 10% of the people in the U.S. over age 65 are going to get Alzheimer's disease. In a cohort like this, we might double that, maybe up to 20%. So it's not that everybody in the cohort has the disease and we're just watching it. We don't know who in the cohort is going to get symptomatic Alzheimer's disease. And so we are trying to take in as much information about the cohort as we can. We're trying to find out their medical history from them. They fill out these large packets of information on their health histories, on their diets, on their sleep habits, on their physical activity, on their cognitive activities. And we piece all of this together with the cognitive testing that we do every two years. And we also collect laboratory tests and blood. We collect a bunch of blood and spinal fluid of people who are willing to to bank for future studies. And we're finding some wonderful things with that precious fluid. But I'm really inspired by our participants. I really am. I enjoy interacting with them. I get a sense of urgency when I'm around them because they're committed to the cause. Our retention rate is actually pretty high. And we just have a a really dedicated group of volunteers.

Nathaniel Chin: I think dedicated is the right word too. I have had the privilege of working with the WRAP participants, and they really are loyal to the cause. They're loyal to the study. They're very much involved in the research aspect. They offer their ideas, they offer their history, and most certainly, they do offer their bodies to be studied. So what makes this group of research participants so unique and valuable when we think about Alzheimer's disease research?

Sterling Johnson: I think it's having that family history puts them at slightly higher risk. So it's what we call a risk-enriched cohort. And again, we don't know who's going to get the disease necessarily from this, but we know that the cohort is enriched so that together with the high retention rate and now the actual fairly long time that we've been studying these people is what makes this study so valuable and unique. And in recent years, we've actually, the past 10 years we've been adding on biomarker visits. And that means when funding is permitted, we ask our participants to undergo these fancy PET scans, these fancy imaging techniques, and the information we've gotten from that has also just greatly leveraged the study and really accentuated the value of the entire study.

Nathaniel Chin: And it's really helped us understand, again, this process of Alzheimer's disease or at least identifying it. And so what I'm hearing is that we're very lucky to have the WRAP study here in Wisconsin. Can you tell us about some of the major scientific findings that you and your research team have really been able to uncover?

Sterling Johnson: Sure. The WRAP study has been in the hands of many researchers here at UW and elsewhere. Some of the things that we've found here at UW are first of all, the time course of these biomarkers, we're finding that people do indeed, many people who get these PET scans do indeed show signal earlier in life than you might think. And it leads to the question of what's going to happen. Will they eventually have symptoms? What's going to help us predict when they get symptoms? So we're in many ways waiting to see, you know, we're in a observational longitudinal study and part of the game is to observe and learn what we can as we observe. And it takes a long time for that. But in the meantime, we're taking advantage of all the data that they've provided. We've found relationships with many of the lifestyle that our participants have given us information on. Like we have found a relationship between hypertension and cognitive decline, and that's related to the biomarkers. We found relationships with physical activity and cognitive decline. We found relationships with sleep. And some of these relationships are subtle or small, but they still might be meaningful, especially in a cohort where most of the people are normal and will stay normal. It's remarkable that we're seeing these kinds of relationships at all in such a healthy cohort. And we've had other very interesting findings too. We're really pushing the neuropsychology technology to see how early we can identify cognitive impairment. The traditional clinical ways of identifying cognitive impairment are robust, and they work very well, but maybe we can find more information by asking the questions in a slightly different way. So that's some of the things that we're doing with the study. We publish roughly, I would say anywhere from 15 to 20 papers a year on the WRAP study, just from our local group. And then there's a number of projects going on throughout the world that WRAP has participated in.

Nathaniel Chin: And I'm glad you said that, because the data collected from the WRAP research participants it isn't just a secret here in Wisconsin for our own researchers, this data is actually available to researchers all over the world who can use it to test their ideas and conduct their own studies. So could you tell us about a couple of those studies that have used WRAP data from outside of Wisconsin?

Sterling Johnson: Sure. Yeah. In fact researchers can go to wrap.wisc.edu and fill out an application form to get the data. We like to share the data. We want to share the data. This is what the National Institutes of Health wants from us, and I think it's what our participants want from us as well. They want this data to be put into the right hands of highly qualified scientists and help us come to answers as fast as we possibly can. So, yeah, we've been sharing this data across the world. Our colleagues in Australia have our data. We are part of a consortium with Johns Hopkins University and the Washington University in St. Louis, the Baltimore Longitudinal Study on Aging, and our friends in Australia, the Australian Imaging and Biomarkers and Lifestyle Study. And we're pooling our data in order to address questions of high scientific impact that we wouldn't have been able to get to as a single study. Just this morning I was emailing with some colleagues in California who were interested in getting the data and I gave them our website — wrap.wisc.edu — and they're going to fill out a request form and we'll try to collaborate with them. The National Institute on Aging, like I said, part of our application for the grant is to have a data sharing plan. So we have a data sharing plan, and we have certainly the intent and a little bit of the infrastructure needed to share this data throughout the world.

Nathaniel Chin: I think it's important for people in the community to know that it is through collaboration that we anticipate more and more findings will come and working with other researchers across the world. But also, I think going back to one of the things you said, yes, this research is about understanding the disease through biomarkers, through hard science, but also this research is about helping people. So you've mentioned earlier diagnostic techniques, learning how to identify changes in human beings, and it's something, of course I'm interested in too, is ways that we may potentially be able to reduce risk. And it's really only through the participants and their willingness to share information and be a part of the study that we could figure out if something is actually true or maybe just good for us.

Sterling Johnson: Yeah. They understand that this research may not benefit them directly. It's probably going to benefit their children, hopefully, and the generations to come. So their dedication to this has been, I think, one of the highlights of the whole project for me. But yes, you're right. The findings may not come to fruition right now. We hope they do. We hope that we can work fast enough that we can help the participants that we have now. And one thing that we're able to do with this is use their information, and by information I mean looking at the rate of change we see on their cognitive tests and on the biomarker tests that we're collecting, and we want to see if we can use that to power, or plan I should say, the next round of clinical prevention trials. And that's something where I really hope that WRAP can become more involved with, because I think prevention research is really where this field needs to be. And where WRAP is really excelling and can help the field in a big way.

Nathaniel Chin: Now, one very exciting and very fresh idea that your research team is pursuing is something that I've been involved in as well. And that's this research into amyloid chronicity. Now, amyloid is one of the key proteins in the development of Alzheimer's disease, but this idea of chronicity is relatively new. So this is a very technical topic, I'm going to ask that you be brief and give us a nontechnical summary of what you guys are finding so far.

Sterling Johnson: Well, chronicity is an interesting word. It has to do with just how long a chronic disease has been in play. It has to do with the fact that Alzheimer's disease is a chronic disease and it's not something that you can just say how long has the disease lasted. Chronicity implies that it's got that chronicness to it and that this is a disease that for all intents and purposes is not going to go away. It's not an ailment that has a duration and has an end point. The end point for this is dementia and beyond. So we use that term chronicity to gauge how long a person has had amyloid in their brain. And we've used some algorithms, some statistical approaches, to look at the people who've had multiple scans over the last 10 years, and we've been able to see how the rate of change happens in people. And from that we can trace it back to when, we can interpolate basically, to when they became amyloid positive. When the amyloid in their brain crossed some threshold where we think it is of some significance now. And so we're calling that period between when they became positive and how old they are now, the amyloid duration or amyloid chronicity. And that's going to help us a lot because the current practice in the field is to just determine whether someone is amyloid positive or not. And with this piece of information, we can tell not only that someone has amyloid in their brain, but how long it has been there. So when we think about prevention trials we might want to equate people for how long they've had amyloid. Somebody who has only had amyloid maybe six months or a year, might be in a very different cognitive space than someone who has had it in their brain for 20 years already. They may be eminently declining, whereas the person who's only had it for one or two years may have many years left of good quality of life. We're also finding with this research that the disease doesn't begin at the same time in everybody; there's a few people who might get it in their early fifties, and by getting it, I mean become amyloid positive, and there's other people who might convert to becoming amyloid positive in their seventies or eighties. And if we think that you have to live with amyloid in your brain for 20 or more years before the symptoms ever manifest, it's giving us a really powerful beacon of who we should be studying and who we should be focusing on if we want to prevent this disease. So chronicity is turning out to be a very important concept. We just had a paper accepted for publication just last week on our first analysis of this chronicity concept, and we think there'll be many more to come. And we think it will help us understand resilience, it will help us understand risk, and more importantly, it will just give us some precision of what we're dealing with in the pre-symptomatic time frame.

Nathaniel Chin: I want to tell our listeners that there's actually going to be more on this topic because we will have the lead authors of the study on the podcast shortly to talk about amyloid chronicity. So please stay tuned to that. Now, Sterling, in closing, I want to ask you something that I ask a lot of our guests, but as a brain health expert researcher, what do you do in your personal life to promote brain health?

Sterling Johnson: You know, with everything that's happening in the news media about how you can do this behavior and stave off Alzheimer's disease or dementia, it's enough to make us all even more health conscious and health heightened, and maybe a little health neurotic. And I have no trouble getting into that space, that's just my own mentality, but some things that I do personally, I try to exercise as much as I can. You know, three to five times a week, I'm either jogging on the treadmill or outside when the weather permits, riding bikes or doing other things outside. I try to eat well, try to avoid sugar. I try to eat good things, and that's sometimes, what a good thing to eat is in the eye of the beholder. But I try to eat healthy things I should say, and just stay mentally active. Fortunately my work, this work, keeps me going a lot, and so I try to do things that are not always work related but something else to relax a little bit every now and then. But those are some of the things I do.

Nathaniel Chin: Well, thank you, Sterling. And I'll say one of the things you didn't say, which I want our listeners to pay attention to, is that you didn't mention sleep. And that's probably because Dr. Johnson doesn't sleep that much. But for the rest of our listeners, sleep is really important too, so try to get more than seven hours. But that's for today. Thank you for joining us on Dementia Matters, Dr. Johnson, and I'm sure we'll be having you on again.

Sterling Johnson: Thank you.