It Takes Two to Tango: The Importance of Amyloid and Tau in Cognitive Decline

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Show Notes

Drs. Koscik and Betthauser referenced two recent research papers in this podcast.

"Amyloid and tau imaging biomarkers explain cognitive decline from late middle-age"
Brain, Volume 143, Issue 1, January 2020, Pages 320–335

"Amyloid duration is associated with preclincial cognitive decline and tau PET"
bioRxiv, The Preprint Server for Biology, posted September 23, 2019

Transcript

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NATHANIEL CHIN: Welcome to Dementia Matters, a podcast presented by the Wisconsin Alzheimer's Disease Research Center. Our podcast is here to educate you on the latest research, caregiver strategies, and available resources for fighting back against Alzheimer's disease. I’m your host, Nathaniel Chin, thanks for joining us.

NATHANIEL CHIN: Today on Dementia Matters my guests are Rebecca Koscik and Tobey Betthauser, both PhD researchers at the University of Wisconsin-Madison. Dr. Koscik is a senior scientist in the Wisconsin Alzheimer's Institute and Wisconsin Registry for Alzheimer's Prevention (WRAP) study, where she has studied Alzheimer's disease since 2003. Dr. Betthauser is an assistant scientist researcher in the Wisconsin Alzheimer's Disease Research Center, where he studies advancements in brain imaging and cerebral spinal fluid biomarkers of Alzheimer's disease. They are here with me today to discuss their recent research on a new concept in Alzheimer's disease research and that is amyloid chronicity and amyloid and tau trajectories. Welcome to Dementia Matters.

REBECCA KOSCIK: Thanks.

NATHANIEL CHIN: Before we delve into the science, I want to start this interview with a question I ask a lot of guests and that's what got you interested in this field of Alzheimer's disease and dementia research. Dr. Koscik, why don't we start with you?

REBECCA KOSCIK: Thank you. That's a really interesting question. I've worked as a statistician since 1989. But after working in statistics, I realized I wanted to do more and I went back and got my PhD in educational psychology with an emphasis in school psychology. I learned a lot about cognitive assessment and developmental occurrences at the young age of the developmental spectrum. Then I realized I missed research and there was an opportunity to come back to the department of biostatistics because they needed a statistician who also understood cognitive assessment data. So that was how I came back into research at the medical school and I started on a cystic fibrosis project with adolescents.  Then I came on board with Dr. Sanjay Asthana's research group and I began working in Alzheimer's disease. And that's how I got here.

NATHANIEL CHIN: Started with the young and are ending with the old.

REBECCA KOSCIK: Yes. There's a lot of similarities between the two ends of the spectrum.

NATHANIEL CHIN: And cognitive milestones, which is true throughout our entire life.

REBECCA KOSCIK: Exactly.

NATHANIEL CHIN: Statistics are important in research. They're extremely important when studying diseases of aging where we're looking at changes over decades and not just a simple experiment. In Alzheimer's disease how we analyze data is critical. Can you share with us what you've learned from all of your work on Alzheimer's disease and the importance of using good statistics?

REBECCA KOSCIK: Yes, that's a great question. In fact, I'll expand it a little bit. It's not just good statistics but it's good statistical design. Making sure we have enough people in a study to answer the question we're interested in is important to know if the results we got are reliable indicators of what we're interested in. That’s sort of in general about statistics. But in Alzheimer's specifically one of the really exciting things we get to do here because of the WRAP study and the Alzheimer's Disease Research Center’s (ADRC) parallel studies is we get to look at what's happening before clinical symptoms appear. With good statistics we can detect really subtle early changes and can help figure out the implications for clinical relevance. We can also help learn the earliest changes in the biomarkers that are related to the brain pathology associated with Alzheimer's.

NATHANIEL CHIN: On another part of the research, Dr. Betthauser, how did you get into your particular field within Alzheimer's disease research?

TOBEY BETTHAUSER: Sure. I started out as an audio engineer, which doesn't seem like it would have many parallels to Alzheimer's, but I'll get there. Around 2010 I decided to get out of it. I wanted to do something that was a bit more impactful. I didn't really feel like my contribution was much making music all day long. I got into physics and then wanted to go into something more applied, so medical physics, which is more or less the application of physics to medicine. A lot of that is in the worlds of oncology and also any medical imaging scan you could think of: An X-ray, a CT, PET imaging (positron emission tomography imaging), which is really where my background is. I was fortunate to end up in Dr. Brad Christian's lab here at the University of Wisconsin. He does a lot of really impressive developmental work on PET radio tracers that we use to attract different brain targets. The field and the ADRC here were just getting into tau imaging. So, I was able to get a lot of experience there looking at tau, which is one of the protein aggregates that we look at in Alzheimer's disease. It was a little bit of serendipity and a little bit of purposeful drive once I got into it. Then with Alzheimer's, I have a family history on both sides of my family. It's very nice to work on something where you can make a direct impact.

NATHANIEL CHIN: Because we can't actually go into people's brains, we need to have a way of studying the brain in live-time that's protective of them, but also helpful to us in figuring out what changes are happening that are normal versus abnormal, and over time, what those abnormal changes mean. And that's something that you in particular would look at.

TOBEY BETTHAUSER: Right. To add to that, I like to draw parallels to cancer research. The thing with most cancers is that they happen on a truncated timescale. From the time you can detect a cancer to when you reach some clinical end point, it could be a matter of three to five years. In Alzheimer's disease, we're talking decades. We were in it for the long haul as Rebecca suggested. You know, we really need studies that are designed from the initial phases to look at these things. Then we have to figure out what they mean, right? We can look at these amyloid and tau biomarkers and say whether they're elevated or not, but we need to get that context of what that means clinically for somebody now or five years from now. Then, of course, there's a bunch of implications for clinical and prevention trials and things in that world as well.

NATHANIEL CHIN: When talking about research dealing with amyloid PET scans in particular, I often hear people refer to elevated versus non-elevated, or positive versus negative. Some people even have said sub-threshold versus over-the-threshold, which makes it all very confusing for people not in the field. Can you talk a little bit about the amyloid PET tracers themselves, how they work and what you are actually measuring when we get these scans?

TOBEY BETTHAUSER: Right. The goal is to track the pathological process. In pathology we can look under a microscope and we can see these changes. So again, drawing the cancer parallel, if you go in for a tumor biopsy, a pathologist can put that on a microscope, they can say you do or don't have cancer. With the brain that's much more difficult. Obviously we can't be taking tissue sections of the brain during life. So, we need imaging techniques and non-imaging techniques to be able to look at the biological markers of a disease process, in this case proteins. With PET tracers, they're no different than any other drug except for there's much less of it when we inject it. There's a radioactive isotope attached, and we can detect the radiation that emits from that isotope. What that allows us to do is to take a drug, inject it into a person, then we can follow the distribution of that drug throughout the body, and in this case, the brain. We can do some pretty nice, fancy methods to determine the amount of amyloid or tau within some part of the brain, some region of the brain. As it comes to detection, there are many processes that can affect detection. That’s one of the things that we're really starting to learn with this longitudinal analysis that both Rebecca and I have been working on, where that meaningful signal is. It's similar to what Rebecca was saying about noise in the cognitive data. There's noise in any data. We have to understand what that noise is and what's meaningful signal in that noise and how to pick that out.

NATHANIEL CHIN: Two things about that answer I want to clarify. One, an isotope, is that just a chemical?

TOBEY BETTHAUSER: That's like an element on the periodic table. But it's radioactive. The types of elements that you use for PET imaging are not the stable isotopes that you see on the periodic table of elements. Those will sit there indefinitely in some form forever. But with radioactive isotopes, they undergo radioactive decay. There are very specific physical processes that determine how fast that happens. But they emit particles when decay and we can detect those particles.

NATHANIEL CHIN: So you want them to decay so that you can pick up the signal, right?

TOBEY BETTHAUSER: We need them to decay.

NATHANIEL CHIN: Second, because you've said the word a couple of times and I want our audience, especially our participants, to hear this explanation. Radioactive, usually it's thought of as a scary term, but in this regard, we're not fearful of the radioactivity.

TOBEY BETTHAUSER: Right. There are a number of studies that happen before any kind of PET tracer makes it to any human research. There are toxicology studies that happen basically in a Petri dish or in animal models. These give us some indication of the safety of the tracers we're injecting. That includes like what a typical drug would have. If you're developing a new drug like aspirin or something, you need to know at what level is it effective, but also at what level is it dangerous. All of those studies happen prior to getting into humans. Then on the radioactive element of it, we do what are called dosimetry studies to understand how much that radioactivity is effectively delivering a radioactive dose to the patient, or in this case participants. There's a challenge in radiation dosimetry of very low levels of radiation. It's hard. You can't really do a proper study in humans. You can draw parallels to things like flying on a plane from New York to Los Angeles or other types of radiation exposure that are equivalent to a PET scan that are thought to be safe.

NATHANIEL CHIN: I want to move into this very important publication. You have two of them. I want to start with the one that happened in Brain. I know the other one happened in what exactly?

REBECCA KOSCIK: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring journal.

NATHANIEL CHIN: Let's start with the one in Brain and I say it’s important, but really it's quite novel what you guys are showing. If we could start by explaining to our audience what exactly you were looking at and then what you found.

TOBEY BETTHAUSER: Sure. I think it's important to understand the timeline of when things became available. Rebecca mentioned the WRAP study being around since around 2005. We have all of this cognitive data that's been collected over this period of 10 or more years prior to when some of these PET tracers became available. One of the PET tracers that has only recently become available is MK6240 and this looks at tau tangles. We’re just now getting a picture of what tau looks like in the brain with this radio tracer. That was where we anchored the time point. We said, okay, people had this tau scan and then they had eight or 10 years of cognitive tests prior to that tau scan. Based on their tau scan and their amyloid scan we can determine people that have elevated levels versus not-elevated levels of amyloid and tau based on imaging. Then we can look backwards in time and say, how did these people perform in the previous eight years before we had these PET scans. The big research question we had was, one, did these people perform differently over time? We had four groups, people that could be negative for both amyloid and tau, people that can be positive for just amyloid or just tau, or positive for both amyloid and tau. We compared how people in those four groups performed over time in that previous eight year period. We wanted to see if what we're calling cognitive trajectories, so their change over time, if those differed between those biomarker groups. And if so, how were they different?  That was really the main analysis. This was 167 people from the Wisconsin Registry for Alzheimer's Prevention, and the imaging was mostly conducted under Dr. Sterling Johnson's Predict study. What we found is that people that had elevated levels of both amyloid and tau in imaging had been declining much faster compared to any of those other groups and that those other groups were not different statistically in longitudinal cognitive performance. It’s kind of a first step in this early detection idea. All of these people were cognitively unimpaired when they started the study, we could say normal cognitively.  We found that only six of these people had mild cognitive impairment (MCI) at their PET scan and all of those [people] pretty much just became MCI at their last cognitive visit. So, what we were seeing is that these cognitive changes were occurring several years before the PET scans. These people that had both higher levels of amyloid and tau at the end of the study had been declining for several years before. We did those imaging scans. It’s kind of a first step towards understanding what these biomarkers tell us about how somebody is going to perform related to Alzheimer's disease. It suggests that people with both amyloid and tau are declining faster in cognition even during this phase of disease where they haven't met clinical levels for cognitive impairment.

NATHANIEL CHIN: How does this study relate to the most recent publication that you guys have had in Alzheimer's and Dementia?

REBECCA KOSCIK: The most recent study we published is a paper where we're looking at translating this measurement of how much amyloid is in the brain at any given time to an estimate of how long has amyloid been present in the brain. Because we have a lot of people, a little over 70% , who don't have evidence of amyloid in their brain yet. And then we have people with varying levels. This earlier conversation about PiB-positivity or amyloid-positivity versus sub-threshold or things like that, there's a ton of interesting questions that can be asked: Is it being over a level that matters or is it how long it's been present in your brain that matters? Because there is a cascade theory in Alzheimer's disease that the pathology begins with amyloid. Or at least one of the earliest things. And then because of that, other things may begin to happen. This most recent paper, it's work that Tobey, Dr. Johnson, I and others have been working on and thinking about: Can we translate this measurement of amyloid into a duration of burden? Because we think that understanding that might improve our clinical trial design by selecting people that are in a critical window or that some treatments may be more effective at this stage of amyloid duration versus others. It will help us understand which pathology is developed first and second. With the tau and the amyloid imaging work that Tobey's doing now, we're beginning to see that for a lot of people there's a gap between when amyloid occurs and then when tau occurs. It just opens up the opportunity to look at the questions from a slightly different perspective.

NATHANIEL CHIN: Do we have any findings or any significance to whether or not chronicity, having amyloid for longer, has any impact?

REBECCA KOSCIK: Yes. In that paper, what we ended up showing was that the longer you have amyloid in your brain, our estimate as long — I just have to put this in — it is highly related to how much amyloid is measured, but it's a different way of looking at it. Having had [amyloid] longer makes a person more likely statistically to be exhibiting declines. Similar to what Toby described either to a point of mild clinical impairment or cognitive impairment, or just subtle declines relative to others in our study that say this is a statistical difference that we think is showing real change. We also saw a relationship between this amyloid chronicity or duration and some of the measures of tau. That’s where we started seeing some of that gap of maybe eight to 10 years after PiB chronicity. It depends on how you measure it, but we know that there's a lag between when the amyloid is detectable and when the tau is detectable.

NATHANIEL CHIN: You wouldn't really be able to ask these questions or answer them if you didn't have people coming in year after year, almost two decades.

TOBEY BETTHAUSER: I think you hit on really the key point. Especially the chronicity work, but even the Brain paper, these things aren't possible unless we follow things over long courses of time. We're really learning that this amyloid accumulation period is several decades. Two to three decades, maybe more than that. And that's just what we can detect with PET imaging. We also know that there's stuff that's happening that we can't yet detect with PET, for example. But it's one of those things where you can't just look at a single snapshot in time across a bunch of people and put it together. You really need to know how people change through the course of a disease and that's really what the WRAP study and the Predict sub-study are really designed to do.

NATHANIEL CHIN: This chronicity makes a lot of sense to me from a medical perspective because we know that when you say, for instance, a person has diabetes, having that diagnosis matters, but knowing how long they've had that diagnosis, how long they've had issues with sugar, how severe those issues have been in the past, it all varies over time, but it all matters. It makes sense to me at least as a non-amyloid specialist that this would be an important piece of information. The other thing I would like to end with is that question of how some people can have high amounts of amyloid and not develop tau. I think it’s important because as a clinician, this potentially is my place of intervention: Are there certain things that people are doing that are building resilience to that amyloid protein and preventing tau? Now that's all speculation, but I think it's important that we have that question because that is something that people can do without a medication. They can do it on their own. I would like to end by asking each of you, what is one thing that you prioritize about your life that you think could be building that brain buffer or reducing insults to the brain that you are doing intentionally?

TOBEY BETTHAUSER: Sure. Probably two things to add there. I would say AD researchers tend to not do a great job of following their own advice. That's probably an overgeneralization. I think the research is pointing to two kinds of things. There's a biological pathway, at least in amyloid; that timeline and that pathway really seemed to be pretty robust to a lot of external influences. I think that's where Rebecca and I were really surprised to see some of these findings. No matter what kind of things we throw at it, your health style, things that you eat, how much you sleep, all these things, it doesn't seem to move that amyloid much, but that doesn't mean it doesn't affect cognition. Right? They're intertwined, but they're not connected in a way that they don't impact each other, and other things can't impact them. To that point, there are plenty of things you can do to improve your cognition. Sleep – which with young kids and research, I don't get much of, exercise, diet, you try to supplement some of these things to at least clear up your mind so you can think better. Those things maybe do or don't affect the biology. Those are questions we're still investigating, and we need answers for. These differences in two people that have the same level of elevated amyloid and one of them has tau, one of them doesn't, why is that different? We don't know that answer yet.

NATHANIEL CHIN: So that's a good way of avoiding answering my question. Rebecca, how about you?

REBECCA KOSCIK: I like to prioritize getting exercise and doing things. Exercise, I find fun. I walk a lot, but I walk with friends usually and that provides some social engagement, too. I play ultimate Frisbee with my daughter and a group of people. I find that exercise is really good for feeling, thinking more clearly.

NATHANIEL CHIN: Okay. All right. And fun is the right word cause both of you smile a lot and you enjoy your work and you're passionate. So perhaps there's something about purpose as well. With that, I'd like to end, but I do want you both to come back as these results come in and we have more to say about amyloid chronicity, amyloid and tau and how a person is doing over time.

REBECCA KOSCIK: That would be really fun. Thank you so much for the opportunity to be here.

TOBEY BETTHAUSER: Thank you.

NATHANIEL CHIN: Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center. The Wisconsin Alzheimer's Disease Research Center combines academic, clinical, and research expertise from the University of Wisconsin School of Medicine and Public Health, and the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. It receives funding from private, university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's disease centers. This episode was produced by Rebecca Wasieleski and edited by Bashir Aden. Our musical jingle is Cases to Rest by Blue Dot Sessions. Check out our website at adrc.wisc.edu. You can also follow us on Twitter and Facebook. If you have any questions or comments email us at dementiamatters@medicine.wisc.edu. Thanks for listening.