AGS Alzheimer’s Disease: New Diagnostic Technologies and Treatments Podcast

Role of Fluid Biomarkers in the Diagnosis of Alzheimer’s Disease

• American Geriatrics Society • Season 1 • Episode 8

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Join Dr. Michael Harper, Professor of Medicine at the University of California, San Francisco and Dr. Cindy Carlsson , Professor of Medicine Geriatrics at the University of Wisconsin School of Medicine and Public Health and staff physician at the Madison VA Hospital Geriatric Research, Education and Clinical Center (GRECC), Madison VA Memory Assessment Clinic, as they the role of fluid biomarkers in the Diagnosis of Alzheimer’s Disease.

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Dr. Mike Harper:

Well, hello and welcome. My name is Michael Harper. I'm a geriatrician at the University of California, San Francisco, and I'm really pleased to be moderating today's podcast, which is part of the American Geriatric Society's new educational curriculum on Alzheimer's disease, new diagnostic technologies and treatments. We designed this curriculum to support both experienced clinicians and geriatrics fellows as we all try to navigate this sort of rapidly evolving landscape of Alzheimer's disease diagnosis and treatment. I think it's important because as these new technologies and therapies continue to emerge, it's more important than ever to stay informed and prepared for this future of dementia care. And today I have the pleasure of speaking with Dr. Cynthia Carlsson. She's a geriatrician and the Louis A. Holland Sr. Professor in Alzheimer's disease at the University of Wisconsin School of Medicine and Public Health. There she treats veterans living with dementia, and she's also the clinical core leader in the Wisconsin ADRC and director of the Wisconsin Alzheimer Institute. Among her many research interests, she studies biomarkers for Alzheimer's disease. And apropos of that particular interest, I'm very grateful to have the chance to talk with you today, Dr. Carlsson, about your module on the role of fluid biomarkers in the diagnosis of Alzheimer's disease. So, Dr. Carlsson, welcome.

Dr. Cindy Carlsson:

Thank you so much, Dr. Harper. It's a great opportunity to be here. So I really appreciate your leadership of this course. This is very important for us as geriatricians, both practicing and up-and-coming geriatricians.

Dr. Mike Harper:

Yeah, totally, totally agree. So let's start. So I think it's fair to say that for many of us, and I'll include myself, that are not as immersed in this world of Alzheimer's disease and related dementia research and say clinical care as someone such as yourself, the pace at which the diagnostic tools are emerging can feel a bit overwhelming. Can you kind of give us some just sort of big picture thoughts about, say, how the primary care geriatricians might think about fluid biomarkers in their clinical practice?

Dr. Cindy Carlsson:

You're absolutely right. It's a big change from how we've always practiced. Because again, a lot of times in the past we'd say this person has memory problems. I mean, look for other causes of their memory problems, but really we, you know, grouped them into a class of dementia. And whether it was Alzheimer's or frontotemporal dementia or any of these other causes, it wasn't quite as important because the medicines we had really just were general medications. So you're absolutely right that the rate of discovery has rapidly accelerated, which is exciting, but also puts out new challenges for us as geriatricians.

Dr. Mike Harper:

I think maybe again, for many of us, this is all relatively new. Can we maybe take a step back and discuss some basic information? For instance, just even when we use the term biomarkers in the context of clinical disease, what are we actually talking about? What are like the key proteins that are most relevant?

Dr. Cindy Carlsson:

Yeah, the key proteins that are most pertinent to the care that we're providing currently are the ones chiefly that contribute to Alzheimer's dementia. So again, previously we just kind of grouped dementias, whether it was Alzheimer's, vascular, lewey body dementia altogether. But now we have a variety of tools. So we've had you know CAT scans for a long time, MRI scans, we've had PET scans, but when with the PET scans, we usually had ones that were a little more general. So they would look to see other certain patterns of low metabolism. But now we have PET scans that can actually tell us if there's protein accumulation. So specifically amyloid protein buildup, tau protein buildup, and we're looking at other types of biomarkers that actually show us where in the brain it's occurring, how much of it's there. But again, the pet biomarkers have only been around really. The first amyloid pet was in 2003. So, you know, go back to Aloise Alzheimer's discovering these markers back in 1906. I mean, they've been around, we've known about them for over 100 years, but it's taken us till you know fairly recently to um be able to actually see these proteins in the brain. And so we're talking about biomarkers, it's really the not just the neuroimaging, but as this unit is going to focus on the fluid biomarkers. So in particular, we focus on spinal fluid, which for many years has been significantly more accurate than the blood tests, but now the blood tests have rapidly evolved. And so that's what's really pushing things into clinical practice and making it more exciting, but also a challenge for us as clinicians, how we're gonna use them.

Dr. Mike Harper:

So I'm glad you brought up the CSF biomarkers, which you mentioned are the ones that came first. What can they tell us? If I was gonna order that, what information do I get?

Dr. Cindy Carlsson:

That's a great question. So spinal fluid biomarkers were discovered first, so they were the ones that had more accuracy because they didn't have all the other proteins in the blood because they're of the blood-brain barrier protecting the spinal fluid from other types of proteins, kind of confounding things. And what the spinal fluid biomarkers can tell us, they can look at the amyloid levels, tau levels, they can look at levels of information, and then what that can do is help us look for patterns. So if somebody has elevated tau levels, that suggests that the neurons have had some irritation, that the tau is being released into the spinal fluid. What's a little counterintuitive is that with spinal fluid biomarkers, the amyloid levels decrease, and that's because we think, in a simplistic perspective, that's that they get deposited into the brains of people with Alzheimer's. So we'd expect the spinal fluid levels of the amyloid to go down, spinal fluid levels of the tau to go up as someone progresses. So not only does it help us look for patterns, like if somebody comes in and has a spinal fluid test that has the low amyloid, high tau levels, does that suggest, you know, if they already have mild cognitive impairment or dementia, is it Alzheimer's that's causing that? But it also can give us a sense of in somebody without symptoms. So that's where the field's going, is that we can also look at these same patterns in people who don't have memory symptoms yet and identify if they're at risk for progression to getting clinical Alzheimer's dementia or MCI.

Dr. Mike Harper:

So I guess when we look at these, it's not just a matter of looking at a biomarker level, but we have to look at them in the context of that relationship between Tau and amyloid.

Dr. Cindy Carlsson:

Yes. And we're finding out too that, you know, for a lot of studies, they looked and saw that elevated amyloid in the brain tissue, so again, lower levels in spinal fluid, that's kind of the first step. But people who have the tau elevation, those are the people who are going to have more likely the cognitive decline. So that's why the combination of the amyloid and the tau together, especially for spinal fluid tests, are so important.

Dr. Mike Harper:

And I guess how specific are these patterns for Alzheimer's disease or other types of dementia? In other words, can they tell us that this person has Alzheimer's disease or not?

Dr. Cindy Carlsson:

They can tell us if it's Alzheimer's disease, but again, what's important for all these fluid biomarkers is making sure that we put it in a clinical context. So, you know, because I could have a 75-year-old patient coming in with no symptoms and just wants to get a, whether it be a spinal fluid test or a blood test and say, do I have risk for Alzheimer's? And they might have, you know, the same levels as somebody who's coming in who has symptoms of mild cognitive impairment or dementia. And so we want to make sure that we're putting that into context because right now there's no approved medications to prevent Alzheimer's, but there are some for treating people who have mild cognitive impairment or dementia due to Alzheimer's pathology. So it's important for us to think through who are the patients we're thinking about using these tests on.

Dr. Mike Harper:

With the emergence of blood-based biomarkers, which we'll talk about in a minute, is there still a relevancy for these CSF wood biomarkers?

Dr. Cindy Carlsson:

There are, because the one thing that's really important to remember as we talk about these biomarkers is that we have very good biomarkers now, both spinal fluid tests and the blood-based biomarker tests for Alzheimer's disease. So amyloid and tau. But we're finding more is that at least 60, 70, maybe even more of our patients who have dementia probably have other pathologies there too. We can't measure those. So if I have a patient who's got elevated amyloid, that might be causing their decline. And chances are it is if it looks like a typical Alzheimer's progression, but there's other pathologies. There's alpha-synuclein and TDP43 and these other newer types of dementia, and we're finding that commonly they'll co-occur in the same person. And so, you know, if I'm trying to use these biomarkers to see what's the best treatment for this person, I have to think through does their picture look like it's really that protein that's causing these decline? So the spinal fluid tests are going to help us look for those other biomarkers, the other diseases are probably co-occurring in the brain.

Dr. Mike Harper:

Got it. Okay, that makes sense to me now. So similar, I have sort of the same questions now because we moved to talk about the blood-based biomarkers. Like, what do they tell us?

Dr. Cindy Carlsson:

The blood-based biomarkers have really evolved tremendously. So again, I've done thousands of lumbar punctures and participants tolerate them well, but um nobody wants one. So they when they come in for our research teams, they're like, I don't want this, but I'll do it. But um for blood tests, and we're all used to getting blood tests. So for our patients and families, people who live in rural areas, this has really opened up accessibility to biomarkers. But again, the blood-based biomarkers are very sensitive and specific for Alzheimer's disease. So the tests, the chief ones are called phosphorylated Tau 217 is one that's more widely talked about now. So P tau 217, and sometimes it's done in combination with the beta-amyloid. So the beta-amyloid 42 is the type of amyloid that's most toxic in the brain. So can the phosphorylated Tau over the beta-amyloid 42 ratio is one of the FDA-approved blood tests. And even though it has Tau in the name, it's really a measure of amyloid. So basically, when the amyloid level gets high enough, it starts irritating the neurons and then they release the P tau, the phosphorylated Tau. So it's really a marker of, you know, the amyloids gotten to this threshold that is going to start causing some neuronal damage that could lead to memory loss. So the blood tests, they align very well with the spinal fluid tests and with the amyloid PET scans. So we're excited that there's something that's going to improve accessibility and something that's more useful for clinical practice than the more expensive or invasive tools, you know, the PET scans or spinal fluid tests.

Dr. Mike Harper:

So you mentioned this ratio. So how is this ratio of tau and amyloid different than the ratio that we look at in spinal fluid?

Dr. Cindy Carlsson:

The tough part about the blood test then is that amyloid goes up in the blood and tau goes up, whereas in the spinal fluid, amyloid goes down as it gets deposited into the brain, but the spinal fluid of the tau goes up. So that's always something you have to kind of catch yourself. Um, but I think as long as we get used to the blood-based biomarkers, which are a little more intuitive, and that elevated amyloid is bad, elevated tau is bad. But the blood tests do a very good job of identifying these changes. And again, they can pick up these amyloid changes in patients even with before they get memory loss symptoms, which is why I think we really need our field as geriatricians to be able to help our patients put them in context, families put them in context so that they're interpreting the information correctly.

Dr. Mike Harper:

Yeah, and I think one of the reasons we wanted to do this series is even if we're not necessarily going to be the ones who are specifically either ordering these tests or interpreting them, that we at least can have the conversations with our patients if we're going to be referring them on to dementia specialists like yourself. You mentioned that there are two. I think the other one is PTau 181. What role does that one play?

Dr. Cindy Carlsson:

So both of the blood tests, so the first one approved was the PTau 217 over beta amyloid 42. Really, the phosphorylated Tau 217 by itself has had very good sensitivity and specificity. I think they added on that amyloid ratio just to make it a little bit, probably boost those numbers a little bit. But whenever we measure amyloid on blood tests or spinal fluid tests, it's a little bit more finicky because the amyloid sticks to tubes, certain types of plastics and things. It's a little bit more sensitive to have levels kind of bounce around just by you know how many tubes it touches and things like that, whereas the tau doesn't do that as much. So I could imagine in the future there may be blood tests that are just that P Tau 217. The other one, the P Tau 181, is just a different length of phosphorylated tau. And so the companies have explored different lengths, and so the the number that's attached to the end is just which particular phosphorylated tau they're measuring. One test was proposed to be used in the context of a complete clinical evaluation, taking into account you know other comorbid factors and the patient's symptoms and all. And then the other, um you know, I think the company and others promoted that it'd be used as a screening tool to see if somebody comes in with cognitive complaints, how much of a workup do we need to do? If it's elevated, their thought was then that would kind of trigger more of an evaluation. Um, but again, I think with either of these tests, there's gonna need to be some, you know, shared decision making, goal setting, um, realistic expectations. And as a clinician, I always think, you know, how is this test gonna change my management or change how the family views this person or how the care they provide? Um, so I think it's you know it's really important that now that we have these tools, we still have to use them in the context of, you know, as a field, do we know how to diagnose dementia? Because even though I wish there were many, many more geriatricians, we're still short staffed for geriatricians and other specialists in dementia care. So if we can get more people comfortable with diagnosing straightforward mild cognitive impairment or dementia, and you know, figuring out how to use some of these tools, that could be really powerful to help, you know, improve early detection on a wider scale.

Dr. Mike Harper:

Let's say you have a younger, healthier person coming to you, they've been referred to you because they have mild symptoms, the progression sort of seems like Alzheimer's disease, so clinically it seems like Alzheimer's disease, and you wanted to sort of confirm that with a one of these blood-based biomarkers. How would you make a decision as to which one or these would you choose, or would you get into both? How would you sort of think about that?

Dr. Cindy Carlsson:

Yeah, that's a great question. I think a lot of people are gonna be faced with that. I think, you know, thinking through, obviously, we always go through the big confounding factors. Do they have sleep apnea? Do they have mood disorder? Do they need to have medications deprescribed? So kind of working through those factors, getting a sense for their family history. So if somebody comes in and they're in their 60s and they have no family history and they're having gradually progressive cognitive concerns, you know, again, looking for other causes as well. But it also, you know, even in people with who don't have family history, there are some who do get younger onset. So, you know, depending on the person's age, you know, it's gonna affect their probability. But um, I think these are useful tools to see, you know, if I've ruled out the other things and it, you know, again, the context of a good evaluation ruled out other conditions, then I think the blood test is very useful. So whether you know I would be initiating treatment or referring someone on, you know, evaluating do they have elevated amyloid and then letting that be part of a conversation for next steps.

Dr. Mike Harper:

If that were the case, does it matter whether you pick the two set PTau 217 or 181?

Dr. Cindy Carlsson:

I'd probably, I mean, I think realistically, the more widely used one is PTau 217. So I'd probably pick that one over the ratio. And again, we're waiting to hear more from the other. I think we're gonna see a lot more of these blood tests um come out and they'll have different specificity and sensitivity. And so I would let that drive what I choose. But right now I'd probably pick the 217, PTau 217, because it's got more research on it to date.

Dr. Mike Harper:

Very good. So one of the things you mentioned earlier is that we can actually begin to see these changes sometimes in advance of someone actually developing clinical symptoms, which I think has created some consternation, I'd say, among our community. So I guess maybe in the big picture, sort of how to how do you think about that? I know that you you describe in your module sort of the kind of couple different schools of thought around this, but one of my uh sort of related questions is if you don't have symptoms and you do have elevations of these that suggest maybe you have Alzheimer's disease without symptoms, do they predict the development of symptoms, for example?

Dr. Cindy Carlsson:

These are they're good tests and they can predict development of symptoms. And you know, I think as geriatricians, it's probably not too soon for us to get familiar with them in the context of somebody who's asymptomatic because there's several big studies going on now, chiefly on anti-amyloid therapies, that in people who don't have symptoms but have elevated amyloids. So we may have, you know, probably in about four to five years, we could have some studies saying in the right person, again, it's only about 10% of our patients who have Alzheimer's dementia who are good candidates for these newer anti-amyloid therapies, but we may have a larger population of our older patients. You know, if these studies show potential benefit of anti-amyloid therapies in people with elevated amyloid before they get symptoms, then I think we're gonna have to be able to switch gears and think, okay, now I have to think about these blood-based biomarkers or the spinal food biomarkers or the PET scans in the context of my patient sitting in front of me who is 80, but their parents live to be 100, they're very fit and active, but they're having cognitive decline, or they're worried about cognitive decline. So we're gonna have to have those conversations probably in the pretty near future.

Dr. Mike Harper:

Is it still fair to say though that for right now it's we're still limiting the use of these to folks that actually have symptoms?

Dr. Cindy Carlsson:

Yes, definitely. I would not do the blood-based biomarker, spinal fluid outside of a research context for people who don't have symptoms.

Dr. Mike Harper:

Cynthia, you've talked quite a bit actually about what these biomarkers can tell us, sort of in what clinical situations that we might think about them. We may talk about that a little bit more. But like any test, I imagine there are limitations to how we interpret them. And I wonder if you could share some of your thoughts about that.

Dr. Cindy Carlsson:

You're absolutely right, said that the blood tests may have some limitations that we should be aware of as clinicians. So one is that if we have a patient who's an elevated creatinine, that could impair clearance of the blood test. And so the amyloid levels may be falsely elevated. If you have a patient who has an elevated body mass index, that could falsely lower the levels. And so that could look like the person's amyloid levels are lower when they really may have some amyloid deposition in their brain. So those studies are emerging and will be continuing to evolve. But we've had some great case examples. We've had to go through where somebody's kind of on the cut point of you know what their amyloid level was on their blood test, and they had some abnormalities in their creatinine, and so trying to figure out what um how does that fall clinically. So again, it's the importance of that clinical context.

Dr. Mike Harper:

So it sounds like we don't have anything like yet cut points for how to interpret a biomarker level based on a creatin level or a BMI, but maybe that's something that comes down the road.

Dr. Cindy Carlsson:

It's should be coming. I think there's not clear cut points. So just get into the cut points for the blood tests overall. But I think um, you know, I think eventually there'll be some cut points to help us better interpret or just repeating tests or again putting them into context of other things like their brain scan results or their cognitive testing or other factors.

Dr. Mike Harper:

Yeah, very good. Um, and I assume those limitations would not be the same for CSF fluid biomarkers.

Dr. Cindy Carlsson:

Correct. The spinal fluid biomarkers, you know, they have their own challenges, but um again, making sure that it's the right kind of plastic. So a lot of spinal fluid collection kits we have have the wrong kind of plastic in the collection tube. So if if it's being measured for amyloid. That might have to be something to consider. But again, the spinal fluid tests aren't as affected by the creatinine clearance or by the volume of distribution, the body mass index, partly because the blood brain barrier does such a good job of keeping them kind of in their own little space.

Dr. Mike Harper:

So we hit on this a little bit, but one of the things I really liked in your module is you gave us a couple of clinical scenarios where you would think maybe these fluid biomarkers could be used. And unlike for biomarkers in or imaging where there's published appropriate use recommendations, we don't quite have that yet. But I think it is still helpful for our listeners to have some idea where some places where you might think about where these could be used.

Dr. Cindy Carlsson:

Yes, that's a great question. And really you've hit on some of the points of that, you know, again, a lot of times we'll have these classic cases of somebody coming in, gradual progressive memory decline. We've looked up all the other factors, no clear other contributing factors causing their memory loss. And so being able to talk through with them what their goals of care are, and if they're considering such, you know, anti-amyloid therapy, for example, want to see what their options are, then you know doing a blood-based biomarker test would be a good way to see do they have you know risk for Alzheimer's pathology. Sometimes, you know, we can do these blood tests, and if they're negative and somebody looks every bit like Alzheimer's disease, sometimes it's another condition like this limbic predominant age associated with TDB43 encephalopathy or late, which looks just like Alzheimer's but comes on later in life, has more prominent memory loss. And so, you know, we're finding that there's a lot of people we thought had clinical Alzheimer's disease, dementia, and they actually don't have that. So that's helpful in those scenarios. We can, you know, someone could guide them to either, yes, pursue anti-amyloid therapy if that's their interest, or to steer them away from that, saying your your dementia is not from Alzheimer's disease.

Dr. Mike Harper:

Let's say you have a similar person, and for whatever reason, you don't think they're a good candidate for anti-amyloid therapy, or they simply, you know, are not interested. Do they still have a role? Or would you just sort of say this the information that we would gain is not going to change our treatment? So we wouldn't do it. Or how are you thinking about them in that context? I think I think this is going to be the questions a lot of us are going to be, particularly if our patients come to us and say, hey, I just want to know.

Dr. Cindy Carlsson:

Right, exactly. Yeah. And you know, I don't think we've mentioned yet, but there's probably going to be direct to consumer access. And so we all have our patients who've done 23andMe or some other genetic tests and bring us the results and ask us what are we going to do with these. And I think we're going to see the same thing. People are going to come in, this is my Alzheimer's test, says I have Alzheimer's disease. What do I do with this information? Well, first of all, it it helps guide therapy. But if somebody's not interested in therapy, so let's say I have a person who wants to get a blood test, they live far away from any infusion center where they could get that anti-amyloid therapy, they don't want to travel that far anyway. And they say, I wouldn't go through with it, but I'm just curious. You know, it can help people plan to some extent. I mean, to know is this a progressive course? But again, it's always a challenge because you can have elevated amyloid and not have symptoms. You can have elevated amyloid and maybe the cognitive progressions from vascular disease or something else. So again, it can tell us some information, but again, it needs to be put together in a clinical package. And so a lot of times we'll use, you know, how someone does in cognitive testing over time to see, you know, what their rate of decline is. Um, because you could have two people with the same level of level of amyloid, and maybe one progresses faster because they also have Lewy body or alpha-sinuclein deposits that we can't detect yet. So so I think there's some rule, but again, I think maybe probing with the patient and their families, what like what are they hoping to really learn from the test and what will they do that with that information? Otherwise, they'll just probably get it on their own and bring it to us and say, now I got the test. So let it yeah.

Dr. Mike Harper:

Guided by chat bots, I'm sure. Yeah, yeah. So it it sounds like you know, like a lot of things. I feel like we're sort of just really much on the leading edge of this, and it sounds like we'll get more clarity probably over time with more clinical experience and folks like yourself who are doing this research. One of the things I really enjoyed, valued in your module was you had a couple of slides that sort of summarize some clinical considerations. I wonder if you could talk with me a little bit about what you think if you could summarize some of those clinical considerations for us.

Dr. Cindy Carlsson:

So I think some of the important clinical considerations are that you know now we're starting to have therapies beyond just treating the cognitive symptoms, or actually having therapies that are focused on the disease. And so as clinicians and geriatricians, we're gonna need to know a little bit more in depth about what the underlying causes of these memory symptoms. So the blood tests are great in that they are more accessible. So again, you don't have to drive to a pet center. They're not as expensive as other types of tests or not as invasive as spinal fluid tests. But again, we still live in a clinical world where a lot of clinicians don't know how to diagnose cognitive decline or MCI or dementia. We have live in a world where we still have a lot of work to do on trying to support caregivers and um, you know, make sense of diagnoses for them. So making sure that we um know what the tests can and can't show us is really important, knowing their limitations, like that maybe elevated body mass index or elevated creatinine could affect the results, but also being able to talk with our patients and families that these tests can be positive even without symptoms. And so um, and they can be positive with other things going on too that we can't measure yet, which is a challenge. So there's a lot of um gaps to be filled in in understanding like what are the other drivers of what I'm seeing in my patient. We have a lot of work to do still on understanding the role of prevention therapies, which hopefully will come in the next five years, but we don't have those yet. So I think helping our patients and families to understand what the tests can and can't show currently, they can be positive even if someone doesn't have symptoms and maybe won't get dementia, but they can predict a person having a higher risk for that in the future. But again, I think getting patients and families involved in research too is important so that we can have more representative samples in our study so we can say, yes, this study participants look like my patients I'm seeing, and and I can trust the test more or less because of that.

Dr. Mike Harper:

Thank you for summarizing those considerations. Any sort of major take-home points that you think you'd want our listeners to go away with?

Dr. Cindy Carlsson:

Yeah, so I think the key take-home points is that we are at a very exciting time for biomarkers and a chance that they're gonna be working their way into clinical practice a little bit whether we like it or not, because like I said, our patients are gonna be bringing these test results to us. But again, I think remembering that these tests can be positive in the people without symptoms, they can be positive in people what's driving their clinical progression, maybe other types of changes, bluey body, TDP43, that they can be altered by the body mass index, the creatinine. But again, that they can help be a really important tool in our clinical toolbox for helping us to tease apart, you know, some of the many factors that can be contributing to cognitive decline in older patients.

Dr. Mike Harper:

It really is an exciting time. I think it's a nervous time for some of us who are sort of learning about this, but you can't ignore that this is not a real step in the right direction for us understanding this. It's now a matter for us to kind of catch up and understand how best to use these tools. Like anything, right? The tool is neither good nor bad, it's how we use it. I want to thank you for taking the time to be with us today, sharing your expertise and your wisdom on this subject, and for the work that you're doing to help us all better understand the role that these new diagnostic tests can play. And as we know, that like I said, we're we're at the beginning stages of this and there's a lot more ahead. So again, thank you very much. Great to have you.

Dr. Cindy Carlsson:

Thank you so much for having me and for your leadership in this project. This is really important for us as a field.

Dr. Mike Harper:

Thanks again.