New Alzheimer's blood test predicts if you have it and when symptoms will start

0:00 Thanks for watching episode #133 of the Doctor Podcast Show, and I'm your host, Doctor Robert Sichert. Please follow and subscribe Dr. Podcasts and please like and repost this and other episodes you watch. We'd really appreciate it. It'll get us even more great guests like we have today. Today's important topic that we're discussing is on everyone's mind, and that is Alzheimer's disease. And today we have an excellent guest, Doctor Suzanne Schindler, who is an expert on that topic. Doctor Schindler is an associate professor of neurology at Washington University School of Medicine in Saint Louis.

0:35 She specializes in Alzheimer's disease, dementias, and memory concerns, which is of great concern to all of us. She leaves the Fluid Biomarker Corps at the prestigious Night Alzheimer Disease Research Center. And we're going to spend a lot of time talking today about biomarkers, which is very important. She coordinates all clinical biomarker testing for the Washington University Memory Diagnostic Center. She's internationally recognized for pioneering work validating blood based biomarkers or blood tests for Alzheimer's, defining their appropriate clinical use, and addressing healthcare disparities in diagnosis and treatment access.

1:14 She has LED Seminole studies on 1st generation blood test for Alzheimer's and continues to shape how these tools move from research into real world patient care. So Doctor Schindler, thanks very much for joining us today on Doctor podcast to discuss this very important topic. We really appreciate it. Well, thank you so much for inviting me, Doctor Sigrid. I really appreciate the opportunity to talk to your listeners about this. Right. So for listeners new to the topic, just about everybody's heard about Alzheimer's, but can you explain exactly what Alzheimer's disease is biologically and how common is it today?

1:49 Is it increasing in incidence? Yes. So the most common question that I'm asked by my patients is what's the difference between dementia and Alzheimer's disease? And and dementia is a broad umbrella term that means a decline in memory and thinking that affects function to some degree. In contrast, Alzheimer's disease is a specific brain disease and it's characterized by brain changes, the accumulation of these amyloid plaques and Tau neurofibrillary tangles in the brain. And it turns out that those amyloid plaques and Tau neurofibrillary tangles start accumulating about 20 years before the onset of symptoms.

2:26 So there's a long period of time where we can see that this pathology is present in accumulating before symptoms occur. And as your listeners probably know, Alzheimer's is very, very common. There are over 7 million Americans living with Alzheimer's disease today. And of course, our population is aging, which means that that number is going to increase. This is a big problem. So it's really important that we learn how to to better deal with Alzheimer's. Right now we hear a lot about risk factors for Alzheimer's.

2:59 Which ones matter most? Is it age? Genetics, like there are certain genes that predispose you to it? Is it lifestyle? Is it vascular health? And how much control can people really have over these risk factors? So great questions. So Alzheimer's is most strongly associated with age. So the older you get, the higher your risk. Of course, there's nothing you can do about that. There's also very important genetic risk factors including APOE. We typically do not test for those because there's not necessarily something you would different do differently if you were carrying one of the variants associated with higher risk at this point.

3:41 And we have increasingly been learning that that lifestyle and vascular health do affect risk for developing symptoms of Alzheimer's disease. And what this means is that we should do the things that we we kind of already knew that we needed to do, like diet, have a good diet, healthy diet, exercise and, and do other things to keep our brain healthy. So, for example, keeping cognitively active, socially active if we're having trouble with our hearing to where hearing aids. So, so things like this, but these are things that we can control to some extent, but some of these are are difficult to to manage as as we all know.

4:26 Right, I've read that controlling diabetes, high blood pressure, cholesterol are also important factors. A large part of population has those conditions. Does controlling them reduce the risk of Alzheimer's or delay it? Yes, we think so. And something to keep in mind is the the symptoms, the cognitive impairment can be related to this Alzheimer's disease pathology, the amyloid plaques and tanar femorary tingles. But of course, we find that people have more than one thing going on often times. And and so in our clinical practice, we see mixed dementia very, very commonly, which means that symptoms are due to Alzheimer's disease, but also exacerbated by other conditions like cerebovascular disease.

5:12 We often see patients who have sleep apnea, which can make this worse. We also have a lot of patients who are taking sedating medications, things like anticholinergic medications, benzodiazepines, pain medications, anti epileptics like gabapentin for example. All of these can contribute to cognitive impairment. And if you do have some of this Alzheimer's disease pathology, it can exacerbate symptoms associated with that. Right now, you mentioned the amyloid and Tau a couple of times as as being important markers.

5:48 Can you explain what those are and how do we know that those are responsible for Alzheimer's? Certainly so. Amyloid and Tau are proteins that all of us make. All of us have. And amyloid, these plaques in our brains are primarily made out of a little protein, mostly one called amyloid beta 42. It's 42 amino acids. And again, we all have this, but as we get older, some of us develop clumps of this protein. And we have learned a variety of different ways, including genetic studies that if you have high levels of this, a beta 42 for genetic reasons or, or other reasons, that you're more likely to develop these amyloid plaques.

6:34 And it turns out that the amyloid plaques are really what define Alzheimer's. So if you don't have amyloid plaques in your brain, you don't have Alzheimer's, period. So, so there, it's very linked to the definition. Now Tau is very interesting and that again, all of us have Tau. It's a cytoskeletal protein. So it, it gives structure to our neurons and it, it seems like Tau is a sensor almost of this amyloid pathology. And as amyloid starts to accumulate in the brain, we see striking changes in Tau and there's, and this is relevant to later, but there's changes in phosphorylation modifications made to Tau including it one particular place in Tau position 217.

7:20 And this again reflects an injury or some kind of response to this amyloid pathology. And over time we see more and more changes in Tau and it accumulates into these little fibrillar structures inside the neurons called neurofibrillary tangles. And when we quantify using imaging, these neurofibrillary tingles very strongly associated with cognitive impairment. So, so you start off with this amyloid pathology and it somehow leads to this Tau pathology. We're still trying to understand exactly how.

7:54 And the Tau pathology is very strongly linked to to neurodegeneration and to cognitive symptoms. Right. So basically these two proteins are excessive in the brain and prevent the nerve cells or neurons from communicating with each other. Yes, and these these interactions are are complicated, but we do think that eventually the these amyloid plaques causes the dysfunction and the Tau and the Tau may be directly damaging to the neurons or reflect damage to the neurons. And then there's other events that occur that we're still trying to understand.

8:31 So inflammation is a big one that people talk about. So but but by that point, the kind of the horses out of the barn and there's there's a lot of downstream changes from this amyloid and Tau pathology that that are quite complex. Right now, you mentioned earlier that this Tau and amyloid accumulates 15 to 20 years before anybody has any symptoms. How do we know that? Is that from autopsies that were done on on people's brains who died from other causes or how do we know that? Yeah. So we've looked at this in a variety of different ways.

9:07 One way that's been particularly powerful is there are people who have mutations that affect amyloid and if they have these mutations, they will get Alzheimer's. And we know about when they will get Alzheimer's based on their family history. So if someone was, if someone's mother was 50 and, and her the, the, the mother's sister was 54, you know, we can estimate that they'll get symptoms somewhere in between like age 52. And then we can look at that person who has the estimated age and onset of 52 when they're 3220 years beforehand.

9:47 And even at that point, we see that these biomarkers of amylin and Tau pathology are starting to change. So, so this, these genetic forms of Alzheimer's have been very informative. And more recently we've been applying a variety of mathematical approaches, again, looking at people who are well before symptom onset and, and seeing how these biomarkers of amyloid and Tau and, and other aspects of, of the biology of Alzheimer's change many years before people develop symptoms. So we've been able to work out this time course and it's actually very consistent across different techniques.

10:25 And, and again, we can see really striking changes really in many different proteins A decade or more before the onset of symptoms. Wow. Now take us through the current diagnostic toolkit that's been around for a while. That's cognitive testing, PET scans, and and spinal fluid tests. What are the strengths and limitations of of each of those? Well, 30 years ago, the only way that you could get a definitive diagnosis of Alzheimer's disease was to have an autopsy. And of course, that's not very helpful to patients at that point.

11:00 So we developed these new tests. So one really the first that was developed was cerebral spinal fluid tests. So you would do a Spinal Tap, collect this fluid and we found that in Alzheimer disease that levels of of a beta 42, that protein that I talked about that clumps into these plaques that those levels go down in the cerebral spinal fluid. And that's because the the protein is clumped together into these plaques and and therefore it's not in the fluid. We find the opposite thing with Tau. So there's total levels of Tau and then there's specific forms of Tau that have these phosphate groups in, in certain places on Tau that we can measure and those levels go up.

11:46 Again. We think this is some kind of response or injury response to the amyloid pathology. And so we've used the cerebral spinal fluid test for, for really over 20 years to help us in the diagnosis, but only in occasional cases. And then we developed PET scans. So with PET scans, you inject someone with a radio tracer, like a label that binds to amyloid plaques in the brain and it has this radio label. So when you do a PET scan, if you have amyloid plaques and the radio tracer is finding, your brain lights up.

12:18 And so you can see this on the PET scan and by using these cerebral spinal fluid tests and, and PET scans, we, we really have been able to diagnose people for, for a while quite definitively with Alzheimer's disease. The problem is that, that most people are not excited about doing Spinal Tap and, and these PET scans are very expensive and can only be done in, you know, pretty specialized centers. So even though we had these good diagnostic tests for Alzheimer's, we haven't used them very often.

12:48 So, so that's that's been a major, major limitation. Right. What about the cognitive testing? Is that specific enough or or can they be abnormal if you have reduced blood flow to the brain or a vascular type of dementia? So the cognitive tests are helpful and we see that there are certain features that are associated with Alzheimer's disease. So what people often refer to as short term memory problems. So repeating questions over and over, for example, misplacing items for getting appointments, remembering recent events, those are things that clinically we often see associated with Alzheimer's disease, but they are not specific really at all.

13:28 And especially early on when people have very mild symptoms, we see that many of those people have symptoms due to something other than Alzheimer's disease. So with with people with mild symptoms, we often find find that about 50% of them have Alzheimer's and about 50% don't. So what that tells us is we really need these biomarker tests to to help us provide an accurate diagnosis of Alzheimer's disease. Right. So let's move on out to the present and future where you've done incredible work. Your team and collaborators just published groundbreaking work in Nature Medicine, one of the top medical journals in the world, actually in the February 19th issue, which is just a few weeks ago.

14:11 And it was predicting the onset of symptomatic Alzheimer's disease with plasma P Tau 217 clocks. Can you tell us what that means specifically? Sure. So we just talked about the fact that we can now detect this pathology of Alzheimer's disease in the brain using spinal fluid tests and PET scans. Well, over the last about 6 years, a number of different groups have developed blood tests for Alzheimer's disease. And some of these blood tests, especially those that look at something called P Tau 217, which is Tau with a phosphate group at position 217, those tests are highly accurate.

14:53 In fact, when we compare them head to So, so we have these blood tests, these incredible tools. Some of them are clinically available. So there's actually about 5 different tests that I can order right now on my patients, which is exciting. And, and the way that we're using them now is only in patients who have symptoms. But as we were talking about earlier, we know that these changes in the brain are happening long before people develop symptoms. So something that has, you know, been of great interest is can we predict who is going to develop symptoms of Alzheimer's disease and not only, you know, if they're going to develop symptoms, but when, right.

15:43 I mean, it's a very different thing. Am I going to develop symptoms of Alzheimer's disease in 10 years or in two years? Those, those are really different things to consider. And so I, I've been very interested in, in how to do this for a while. And 1st we we developed something called amyloid PET clocks and then Tau PET clocks and now we have P Tau 217 clocks. And the basic concept is what we have learned is that once you reach a certain level of P Tau 217 in your blood, that the levels go up pretty consistently across individuals.

16:19 And one analogy to think about this is it's almost like tree rings, right? So every year you lay on another ring if you're a tree. And so if there's 15 tree rings and it's 2025, you know that the tree started to grow into in 2010, right? So you can look back and and think about when this all started. Well with the PTOP 217 because it's accumulating in a pretty consistent way across individuals. We can measure it in someone's blood and estimate when they became positive, when when their levels became abnormal.

16:56 We can only do this within a certain range, but it's a pretty wide range. So if they have extremely high or extremely low levels, we can't do this. But within quite a wide range, we can estimate when they became positive, abnormal for PTO 217. And then what we found is the age that people become positive is strongly associated with the age that they develop symptoms of Alzheimer's disease. So, So what this means is that with a, you know, a blood test, we can estimate when people became positive and when they're likely to develop symptoms.

17:32 You know, the, the major caveat of this is these predictions are still quite rough. So only kind of ±3 to four years. That's still right. Yes. And and that's within research cohorts, but this is just with one single test, you know, with one, you know, blood test. So we we feel quite confident that we can make these estimates better by adding in cognitive tests, other blood tests, maybe imaging tests. So we're working on doing that now. But you know, even with a three to four year error margin, it tells us that these sorts of things are possible, right?

18:12 So that seems like it's critically important because if you're 90 years old, let's say, and it says the blood test says, oh, it's not going to be symptomatic for another five years and not much to worry about. But if you're 60, that's a whole different story that you're going to become symptomatic in three or four years. You need to make arrangements with your family and life and, and things like that. So it seems like this is critically important. Yeah. And again, at this point the predictions aren't good enough that I would want to make individual level decisions.

18:47 But you know we may be able to improve this to to a level where that's possible. The major application right now is for clinical trials. So for for clinical trials, we need to run these within most of them last 18 months and they have to be very large because many people don't develop symptoms over that period. And so we think that the the information insights that we got from the study will will help us to pick out the people who are more likely to progress over that time window. Something that we learned that we weren't necessarily expecting is that the age that you become positive for this PTAL 217 and and when you develop symptoms is quite different for younger and older people.

19:37 So if you're 60, when you become positive, it may, you know, kind of on average took about 20 years before people develop symptoms. But when people became positive when they were older, like 80, it only took eleven years. And this this makes sense as as we discussed, many people have cognitive symptoms from many different causes and as you get older. There's more and more what we call comorbidities, copathologies, other things going on in your brain that makes your brain not as resilient. So it makes sense that you would be more sensitive to lower levels of pathology as as you get older.

20:15 But this is still quite relevant to thinking about, you know, clinical trials and risk for dementia or symptoms generally that a positive plasma P Tau 217 means something different for risk in someone who's younger versus. Older, I see. Now you mentioned there are four or five different assays or companies that offer these tests. Can you do this clock test that you've published on all the different assays, or is there just one specific one? Yeah. So actually in the study we primarily looked at at 1-1 test from a company called C2 N Diagnostics, but we also showed that we can make clocks with these other tests.

20:59 So we looked at a test that is quite commonly offered by Fuji Rebio. We also looked at one from ALS path and one that's called a Jansen Lucent AD. So we looked at at several different tests and we also looked at kind of different measures within the those tests get into the weeds. But basically with, with all of these different measures, we could, we could make these clocks and, and so I think it's going to be, you know, pretty robust. Also, we used two different mathematical approaches to to making the clocks and then they, they agreed pretty well.

21:36 But you know, it's good to look at things in different ways and, and find the same results. So this still needs a validation and more cohorts and more generalized cohorts. So we, we, you know, we're using research cohorts, which are usually healthier, highly educated individuals who are less diverse. So there's, there's a lot more validation that needs to be done. But still you know it seems like this is is working across multiple tests. Wow, that's, that's amazing. Now, how's your work on the fluid biomarker core directly contributed to making these tests safer and more equitable as well?

22:19 Well, many of the validation of validations of these blood tests have, as I mentioned, been performed in these research cohorts that do not represent the general population. But we have really tried to look at more diverse populations as well, especially black Americans and tried to confirm that we get similar results. Basically what we see is that the tests work pretty similarly. What's different is the rate of positivity. So in other words, once you're positive, these tests perform the same, but different groups become positive at kind of different rates.

23:02 And we're still trying to understand that. There's also really lots of interest in in looking at different populations now, both within the United States by cities. There's one called Habs HD that's looking at Hispanics, black Americans and also white Americans. But then globally, so these blood tests are becoming common around the world. So people are looking in China and Japan and Korea and the Middle East all over. And, and I, I think everybody's finding very similar kinds of results. And that is these, these blood tests are, are working well.

23:40 They're not perfect, no test is perfect, but they they really do identify people who have this Alzheimer's disease pathology in their brain and who are likely to be at risk for for worsening cognitive decline. Right now, how accurate or or precise is your clock with these blood tests as compared to previous amyloid PET or talpet or the cerebrospinal fluid tests? Yeah. So it's a a little complicated to answer that question because people so we have done these clocks before with amyloid PET and Tau PET.

24:21 We find that the Tau PET clocks work particularly well. But you know, 11 issue in terms of comparing our results to kind of other approaches that people have used is that people have not really looked at this question in the same way. So what a lot of studies have done is they said, oh, you're biomarker positive, so you're positive for P Tau 217. And they find that people who are positive are at higher risk of developing symptoms. But people have not looked at the wind. So they haven't said, OK, your P Tau 217 level is X, you know, when are you likely to develop symptoms.

25:01 And I think that's because the kind of standard statistical approaches that people have used don't really get at that question. And, and so I think our paper will hopefully inspire people to to look more at that question of when, because when people develop symptoms, it's actually really, really important to understanding what a what a test means and, and someone who's not cognitively unimpaired. Right. Or someone who's not cognitively impaired yet. Right now, here's the key question, who should have these tests and who shouldn't have them?

25:35 That that's really critical and important. That that is a very critical question. So right now in my clinical practice, I only do biomarker testing and individuals who are cognitively impaired. And then the question that I'm asking is, are there cognitive symptoms likely to be due to Alzheimer's disease or something else? In clinical practice, I do not test individuals who are cognitively unimpaired and, and I don't even test individuals who are worried about their memory but don't have any abnormalities on their cognitive tests.

26:10 So they have to have objective evidence of cognitive impairment before I I do those kinds of tests. However, in, in clinical trials and in research studies, we are doing these tests and, and we're trying to see whether we can identify people who are likely to develop cognitive impairment and to treat them with, with, in, in general amyloid targeted treatments to reduce amyloid levels to see if that prevents or delays the, the onset of cognitive symptoms. So, so right now in terms of these tests, we only do them in cognitively impaired individuals.

26:55 We do not recommend them in cognitively unimpaired individuals except in the context of clinical trials and research. What if somebody says one of my parents or my older sister has Alzheimer's and I'm really wanting to know what will you do it or, or you'll say no? So I have always said no and and there's reasons for that. So at this point there's not necessarily anything they could do differently. It's a maybe participate in a clinical trial or research study which I could recommend to them without doing the test.

27:34 And of course we want them to institute kind of preventative measures, lifestyle changes, but they should do that anyway. So, so I have never performed these kinds of tests clinically and and someone who did not have objective evidence of cognitive impairment. On the other hand, I do understand why they would want to know if these clinical trials read out as positive. If they find that these treatments delay, prevent the onset of symptoms, then that really changes everything in terms of the the risks and benefits.

28:13 Right now for primary care doctors who are watching this, family practitioners, internists, what it after people watch this program, they're going to go to their doctor and want to have this test on what? What do you recommend primary care doctors tell their patients? Same thing you just said or or something different? I would not recommend they do these tests and people that are cognitively unimpaired, period. On the other hand, I, I do think especially for older people, especially those older people who have family histories of Alzheimer's disease, who have cognitive concerns, that they should be monitored.

28:52 And if they develop cognitive impairment at that point, that's when you do these tests. So, so that would be my recommendation. So don't do them right now, but monitor. Now, if there are people who are really interested in learning about their risk of developing symptoms and have risk factors, then in that case I would recommend they look at clinical trials to see if they can get involved any of in any of those. And some of those trials and research studies will do this kind of test and disclose the results so so people can can learn about it that way.

29:31 Right. Do you know what the incidence of false positives or false negatives are with with these tests? And are there psychological impacts on people in the clinical trials who had no issues or problems and then they find out they're positive and it tells them in four years you're going to have symptoms? Yeah. So in terms of the the rates of of false positives, it really depends on the population that you're testing. So for example, if you're testing cognitively impaired older individuals who have symptoms that can be consistent with Alzheimer's disease, the number of people who are false positives is quite low.

30:15 But what we call the positive predictive value is, is very high. But on the other hand, if you're looking at younger individuals who are not cognitively impaired, those are the people where if the results is positive, they're more likely to have a, a false positive results. That's again one reason why we don't want to test people who are cognitively unimpaired because there's just this higher risk of, of positives being false positive. So, so it very much depends on what what we call the pretest probability this, this likelihood of false positive if we use it in the appropriate population, which is a cognitively impaired population with very low rate in terms of the psychological impact.

30:59 So obviously a diagnosis of Alzheimer's disease is, is a really big deal. And I, I think it's when, when I return this to patients who have cognitive impairment, they often tell me it's what they expected because they've been worried about this. It has some impact. But, but in many cases with cognitively impaired individuals, it's almost expected. When you're talking about cognitively unimpaired individuals and you tell them they have brain changes of Alzheimer's disease. But the first thing they ask is how sure are you?

31:38 And then, and then the second question is, so how long do I have? What am I going to develop symptoms and, and so that's again, why we were interested in developing those clocks, you know, that I was, was describing to try to answer that question. Again, these are still imprecise for individual level use, but hopefully over time they'll get better and more informative. And, and I, I would just also mention that we find people can handle things better than we expect.

32:12 So we give people lots of information and sometimes bad news and, and most of them cope with it pretty well. There are exceptions and we always worry about those exceptions. But, but most people do pretty well with this information and, and you know, integrate it into their thoughts. This return of results discussion is very important, but when when this is done in the context of research studies and clinical trials where there's a lot of time spent doing it appropriately, people handle the information very well.

32:45 There's been studies of the psychological impact and and really people do quite well. Well, that's good to know. Now if you have someone with a positive test and let's say it predicts 4 years, are you treating now with with these new drugs like Lokembe? I'm an ophthalmologist, but I have already several patients who are being treated with that. Do you recommend those? So right now these amyloid targeted treatments are only indicated and individuals who have cognitive impairment. So I would not recommend doing this test in a cognitively an impaired individual and starting them on treatment if they're close to their estimated age at symptom onset.

33:28 Again, the the predictions just aren't good enough to support that at this point. But more and more importantly, the drug is not, has not been validated yet. As you know, the trials have not read out showing that it's effective. Now I'm hopeful that it will be, I'm hopeful that, you know, a couple years from now we'll be treating patients like that, but we're we're not there yet. Certainly if these trials read out as positive, we will be treating these patients hopefully before they develop symptoms and I expect, you know, hopefully these these treatments will be even more effective in in that patient population.

34:08 But but again, we have to wait for the trials to read out. So currently we we don't have evidence that these drugs like Lokembi will prevent the onset of symptoms if if you have a positive blood test, is that right? No, we do not and and that's why we're doing the trials. That's the the question that the trials are designed to answer. Right. When do you think that this clock testing, the blood based clock testing could become part of routine care for at risk individuals? Do you? Do you have a clock to protect?

34:39 That. Or, or you just kind of have to wait and see what the clinical trials show. Yeah. So I think that if these trials read out as positive, we're probably going to be doing a lot of blood tests on cognitively unimpaired with older individuals.

34:58 And in terms of the how well the clock performs, I mean, right now we have an idea of kind of I think what the basement level is. We'll have to see how good it can get because you know, obviously four year margin of error is not that great. You know, it could be 14 years, could be 6 years. That's too wide of a range. If we can get to one or two years, you know that that would be different. I'm, I'm optimistic in part because we have some new bio, we've been developing all kinds of other new biomarkers.

35:32 1 is called EMTBR Tau 243 that's much more strongly associated with symptoms. So very interested in seeing how that does in these kind of clock models. We also know that symptoms are affected by other pathologies, what we think it is, and that many individuals have other pathologies. And so if we're able to develop blood tests or other other measures, we may be able to further refine our estimates. Really the goal is to, to develop precision individualized estimates that we can use to tailor management decisions.

36:11 We, we do this for diseases like cancer right now. So we are not there yet, but certainly that's what we're, we're trying to get to, to that kind of paradigm where we're taking individual level information, put that into to some kind of model and and that affects what we do next. I see. So if if somebody's in Saint Louis, obviously they can see you For more information or to participate in clinical trials. What what about people in other parts of the country? How can they find out more information about these blood tests and also getting into clinical trials?

36:53 So there are 36 Alzheimer's disease research centers scattered all over the country and they are really a great resource for learning about research and clinical trials. There's also clinicaltrials.gov and clinical trials match. So you can, you can actually go to Google and search for clinical trials that are in your area. So I would, I would certainly recommend those resources. And then, you know, I would just stress that these blood tests are they're not in the future. We have blood tests now for people who are cognitively impaired to help doctors diagnose people appropriately, accurately with Alzheimer's disease.

37:41 These tests could be ordered by any doctor and there's multiple P Tau 217 tests that can be ordered by doctors to help them to decide whether patients symptoms could be due to Alzheimer's disease. What we don't have yet is as I mentioned in cognitively unimpaired individuals, we would not recommend these tests right now. That might, may change in a couple years. So we'll we'll have to see what these clinical trials show. Right, we'll find out pretty soon, I think. Yeah. All right. Well, this has been very informative for me and I'm sure the public out there as well.

38:18 There's lots of new research that's coming out and hopefully we'll figure out a way to prevent Alzheimer's as well in the future. Yes, I hope so. Right. So I want to thank you again for taking time from your busy day to tell us about Alzheimer's and these new blood tests. Really appreciate it. Oh, thank you. It's been great talking with you about this.