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Welcome to the Healthy Brain Toolbox. I'm Dr. Ken Sharlin, neurologist, speaker, author, and host for this show. In each episode, I interview influential people whose work impacts how we live and how we think. My guests are leaders in the health and fitness industry, physicians, scientists. Authors and public servants. Here, you'll find conversations that break down barriers, expand your horizons, and give you the tools you need to protect your health and nourish your aging brain.

Dr. Ken Sharlin: 0:39

Today I am welcoming Dr. Joel Braunstein and he's the CEO and founder of C2N Diagnostics. This is a precision medicine company at the forefront of developing blood-based diagnostics for Alzheimer's and other neurodegenerative conditions. Trained as a physician scientist. Dr. Braunstein brings deep expertise in translating cutting edge research into classical tools. Under his leadership, C2N launched the precivityAD test, and now it's the precivityAD 2. We'll talk about that. This was the first widely available blood test to aid in the diagnosis of Alzheimer's disease. He's also the managing partner at Lifetech Research and has held leadership roles in academic medicine and biotechnology. Dr. Braunstein, welcome to the Healthy Brain Toolbox.

Joel Braunstein: 1:32

Thanks Dr. Sharlin. It's a pleasure and an honor for me to be able to speak with you today regarding some of the innovations and work that we're doing at C2N Diagnostics.

Dr. Ken Sharlin: 1:41

Thank you.

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Dr. Ken Sharlin: 3:36

Let's jump into a deep dive discussion into biological markers, or biomarkers. What are biomarkers and why are they important in the context of Alzheimer's disease?

Joel Braunstein: 3:47

Biomarkers is a general term that's used to identify molecules, indicators, signals that inform about a disease process. And so a biomarker can refer to particles that you can pick up in the blood. It could refer to imaging biomarkers that you wind up getting, let's say an MRI scan or an amyloid PET scan, and you can use those tools to identify the biology of these underlying conditions. Biomarkers have been around for many years, decades, and we've used biomarkers in a number of areas of clinical medicine. I actually come from the field of cardiovascular disease. Trained as a cardiologist and LDL cholesterol, which everyone knows about the importance of cholesterol to inform about the potential risk of a heart attack or future heart disease is a biomarker of, cholesterol metabolism and overall vascular health. Coronary calcium scans another popular modality that's emerged in recent years to help inform about a person's potential risk for atherosclerotic heart disease. When we look at some of the more recent innovations oncology, the field of cancer has been really exploding with innovation around the use of biomarkers. These biomarkers can be genetic. So there can be genetic indicators of someone's risk for disease in some cases, a gene mutation can actually indicate the presence of a disease. You can use tissue biopsies to inform about the stage of a cancer, and then you can use fluid biomarkers like those that are possible to isolate in the blood to not only identify disease or stage of disease, but can even be used to identify the right patient on the right therapy at the right time. And so these biomarkers wind up being really critical tools that are used throughout medicine recently, becoming a standard of care in Alzheimer's disease to help inform about the presence of disease combined with a clinical examination help inform on which therapies might be appropriate for a patient. Then even tracking progression of the disease or a response to therapy. So there's many different applications. And this is C2N diagnosis is a company that has spent, almost two decades focusing exclusively on biomarkers related to Alzheimer's disease in related forms of neurodegeneration.

Dr. Ken Sharlin: 6:25

I speak around the country and I give one common series of slides that I present in a PowerPoint presentation. Is that going back to about 1984? Probably earlier, but that's the date on the slide that I have. The defining diagnostic criteria for Alzheimer's disease was largely clinical, and I still have patients today that think that, the only way to quote confirm the diagnosis is after death and looking at, slices the brain under the microscope. But in fact, that is of course not true. And that's the whole essence of our discussion today. And as there's been an evolution because of the availability of these biomarkers incorporating the presence of what is properly, termed the neuropathological changes of Alzheimer's disease into the diagnostic criteria. And it's now essentially 100% required in order to make a diagnosis of Alzheimer's disease that we have to establish these neuropathological changes. Although it's been a slight shift, I think maybe the pendulum swung a little hard in the direction of the biological markers and left out some subtleties when it comes to looking at the clinical presentation. My most recent read met things more in the middle, meaning you still have to demonstrate changes, but it provides language to help people understand where they are on that clinical spectrum from being at risk to subjective cognitive impairment, mild cognitive impairment to early stage Alzheimer's. Now we're talking about. Blood-based biomarkers and I was, we were talking before the recording started that I've been, using spinal fluid testing or have been for a very long time, although not as much recently because of the availability and the accuracy of this test. But you talk a little bit about the background coming into blood-based biomarkers from. Previously being able to do spinal fluid testing in the community-based setting because although PET scan is available, it's really only been approved under CMS reimbursement for the last couple of years, although that still has existed. And FDA has approved a couple of different amyloid, scan tracers as well as a tau tracer. We can't do tau scanning in the community-based setting. So in that context, move us into 2025 in regard to, how the blood-based biomarker fits into these, gold standards.

Joel Braunstein: 9:06

Very well done in describing the history of Alzheimer's disease clinical evaluation and how we can improve the diagnostic accuracy. Historically, as you pointed out, probably the majority of patients are still only receiving that clinical evaluation. While clinical evaluation is essential, it may not be sufficient to identify Alzheimer's disease, right? Because as you also alluded, studies performed over the last five years of which we've been involved with a number of them have shown the limitations of a clinical evaluation is the only way to evaluate Alzheimer's disease. As that disease progresses and becomes more severe clinical diagnostic accuracy, just using the physician's skills to look at the patient and say, Hey, does this patient meet the kind characteristics that I would expect to see in Alzheimer's disease? Actually diagnostic accuracy is quite high for late stage disease. That's not where we want to intervene, over the last five years, there's just more and more evidence that's piling up to show that the earlier we can identify changes associated with clinical Alzheimer's disease, the more effective the therapies are for the patient. And so this is a kin to the analogy would be identifying. Cancer, it's stage one versus stage three or four, and that the clinical outcomes are gonna always be better if we can intervene earlier. And so what we found surprisingly to the medical community is that patients who present at the earliest stages of clinical impairment, as you pointed out. Is mild cognitive impairment, that subjective cognitive decline, which is a separate syndrome where the patient is presenting and saying, Hey, I just feel like something might be off. Or I had this lapse of memory and I'm concerned, is it normal cognitive aging or something like Alzheimer's It's difficult to discern. standard clinical evaluation led to a misdiagnosis at early stages in one in three, sometimes one in two. So you're talking 30 to 50% misdiagnosis rates at the earliest stages of disease. Coming from cardiology and even what we know about cancer, in what field of medicine are we willing to accept one in three to one in two misdiagnosis rate. And so then the question is, how could we do better? this is where biological markers come in, because Alzheimer's disease has many clinical presentations, and many times can be atypical presentation. So it doesn't fall squarely in line with what you might expect to see on a person's progression along the clinical Alzheimer's trajectory we say, what could we do to enhance that diagnostic accuracy? And that's the role of biomarkers, right? So there's really three primary modalities to get into understanding whether that pathology could be the primary contributor to the clinical presentation. And that's PET scanning, amyloid PET scans, tau PET scans and lumbar puncture, cerebral spinal fluid biomarker analysis. We isolate these biomarkers from the circulating CSF, and then we can analyze it in the lab. But then more recently, in the last five years, starting with the procivityAD test, introduced in 2020 for clinicians to be able to use in the us we now had blood tests that could aid in that diagnosis. So to your point, there's still a raging debate as to what constitutes Alzheimer's disease. Can you make the diagnosis solely based on biomarkers or do you need that clinical evaluation? And the reality is that just like any other field of medicine, it is a combination of the clinical evaluation plus the biomarkers. When you apply that approach, you can get accuracy levels above 90%. That is a game changer. advocacy groups and independent organizations weigh the evidence and guidelines for evaluating a person with early cognitive concerns it does include not only a careful clinical evaluation, which you do every day in your practice, but also the use of a biomarker when appropriate to confirm or basically rule out the presence of pathology. And that combination winds up being really a robust diagnostic solution. Then the question becomes which modality? PET scans, are a great tool, but very expensive. You can sometimes see costs upwards of five to$10,000. For all in costs around facility imaging equipment, tracers or PET or CSF measurements, usually specialists who are accustomed to running those tests or radiologists who need to perform the lumbar puncture. And then we say 85% of all Alzheimer's or dementia diagnoses occur by primary care, What can we do to provide tools to primary care? To elevate that quality of a diagnosis, and that's where blood biomarkers potentially fit that major role.

Dr. Ken Sharlin: 14:19

We were talking about, PET scans, spinal fluid testing. We now have the precivityAD2 test, and that two is there as best as I understand it. Just to imply this is the second generation next iteration. There was the precivityAD which I was involved with. I don't know if you still run it. It wouldn't make a lot of sense to me, but it could be done, what is the PrecivityAD2 test? And even looking back at the AD that focused primarily on the 42 to 40 ratio and a POE status, I think, what are these biomarkers? What do they measure? do they stack up against PET scans and spinal taps, and what information can we get from them are there any limitations?

Joel Braunstein: 15:05

Yep. great question. So PrecivityAD was the first generation test that we rolled out, and that was again, 2020. And that included this plasma, amyloid beta 42 peptide and amyloid beta 40 peptide measurement. We did also look at APO lipoprotein e profile, which is a significant genetic risk factor for sporadic late onset Alzheimer's disease. And we combine that with age. Because yet again, another factor that can increase risk for clinical Alzheimer's disease. And we put it into this algorithm, if you will that combine these three measurements age A POE profile, and then the 42 amyloid, 42 40 ratio to provide a score that we call the amyloid probability score. It provided a likelihood score for a patient having amyloid in the brain. That was a big innovation and it's actually a good test. And that test actually wound up getting a CE mark and still used in a number of research studies including in Europe, but you are correct, the field has moved at a blistering pace. We introduced the second test, the PrecivityAD2 three years later, which kept the A beta 42 40 peptide measurement in blood. But we also combined it with a very unique and interesting biomarker called the pTau 217 measurement that is actually expressed over another fragment of tau protein. That ratio the percent pTau 217, but it's really capturing pTau 217, and then we use that other tau fragment to normalize the P TAU value at the individual level. There's so much diversity in heterogeneity on the way people present. We know there's a number of comorbidities, like significant obesity heart failure or kidney disease. Common with older age, can interfere with the interpretation of a blood test. our specific test was designed to counteract those confounding factors, and we can get over those limitations to provide an individualized pTau 217 measurement combined with the a beta 42 40 ratio. We put that into a new algorithm and that algorithm will provide the likelihood of amyloid pathology in the brain. That test has been tested in tens of thousands of people and we have many publications on it. And there was a very exciting publication that our team was part of, was published in jama in July 2024. That paper studied the performance of the Ity 82 test against Amyloid PET and CSF. The diagnostic performance was virtually identical and so what it showed was that you can use this blood test now in a way that will give consistent readouts trustworthy results that were really only previously possible with Amyloid PET or CSF. This idea of equivalence to PET scans or CSF biomarker measurements was the real innovation. And the good news is that the field continues to innovate. So we're seeing other test developers bring up some of these assays and also showing high performance. We believe the Passivity 82 test is unique because of the unique measurements we make, the gold standard in clinical labs for protein quantitation, and so that analytical performance. Translates to a really highly accurate clinical blood test. And we've been able to demonstrate now that, you can reduce clinical misdiagnosis rates from, 30 40% to less than 10%, and then we can clearly identify whether pathology is present or not. We've published collaborative work with you on one of the studies where we demonstrated that the use of the Passivity 82 test has a very significant impact on clinical decision making and can lead to a significant reduction in downstream testing requirements, much better diagnostic certainty as to whether Alzheimer's disease is present and reduced inappropriate medication prescriptions. So there were patients that we found in that study who were presumed to have Alzheimer's disease. They were giving therapies that are used for symptomatic Alzheimer's management, and then the blood test comes back negative. They were taken off that drug, which is exactly what you wanna do because you don't wanna give a treatment for Alzheimer's disease if the person doesn't have Alzheimer's disease. And we also found that people who might've been a low clinical suspicion. Now with the positive blood test, you say, Hey, now we can. Decide on the right therapy, we had a very profound impact on diagnostic certainty, downstream requirement for additional testing, much quicker diagnosis, and then even appropriate therapy selection.

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Dr. Ken Sharlin: 22:16

As a patient, envision this and I have this test done. What I'm gonna get back is a report includes this percent PT and what's interesting to me, and maybe we can touch on it, is that although it's a reflection of this fragment of the tau protein, that's a biological marker by itself. First of all, it's a very early change, very early biomarker that can be, people are asymptomatic completely and have elevated P TAU. But it's also thought to reflect the evolution of amyloid protein in the brain, though. not a direct measurement of that, which is another subject I'd like to get to in a little bit, because I think that can have a huge impact on clinical decision making in regard to choosing anti-amyloid therapies or choosing between them. But ultimately you're gonna get a, this PrecivityAD this, I'm sorry, the amyloid probability score. I don't think you have a zero.

Joel Braunstein: 23:11

We have a zero to a hundred, yes, we have some scores that report out as a hundred. I'm pretty sure we have a zero. I'll look through our results to figure out how many people have a zero.

Dr. Ken Sharlin: 23:20

So there's an 88 and it's positive, but anything from 48 to a hundred would be considered predictive of a positive amyloid PET scan. I think there were some caveats earlier on in terms of what age is appropriate to do this test or maybe some age related confounding factors. I'll put this in quotation marks old down syndrome adults, 45 to 50 years develop Alzheimer's like presentation. I felt like that was needed in order to move patient or the patient's family into a way, of thinking about where their loved one is and their own life journey. But then again, you do get these individual biological markers and what I found, interested in anti-amyloid therapies, Donanemab, Lecanemab also interested in foundational lifestyle medicine and, its impact we already know based on other studies as well as my own study that was published in a case series that we can. Both improve cognitive functioning as well as biological marker burden by bringing into the fold anti-inflammatory diet, like the mind diet, exercise, sleep optimization, treat, sleep apnea, have a stress resilience. That's been well documented and the nice things about this test I've also found is not only is it helpful on the diagnosis, it's helpful looking at the probability score. As you pointed out, tracking over time, even if you're not doing these integrative approaches, you're treating your patient with anti amyloid therapy, you might look at this. But also changes in individual biomarkers because some people need encouragement. When people adopt anti-inflammatory diet and lifestyle approaches, one of the first things to respond is the 42 to 40 ratio and the percent. pTau 217 does often change as well. That will go down as the ratio goes up. But it tends to drag a little bit and the changes aren't as robust, at least earlier on. But nevertheless, if you have a positive test to begin with, let's say your score is a 95, and then you commit to these changes in your life. And by the way, folks, to be clear, the science is absolutely there. You retest and you're then in 88, you're like I'm still positive. So yeah. Your probability score went down. But more importantly, let's look at the individual biological markers and see what you're accomplishing. the more we repeat the test, we can connect the dots and people see that, Alzheimer's can potentially be a reversible disease. Or at least I say, remission. I haven't followed anybody over 10 years using this test, so I don't know what's gonna happen But I think it's remarkable we can impact not only cognitive function, but changes in biological marker burden.

Joel Braunstein: 26:18

Yes. Yeah. you've touched on key topics as a company our clear intended uses for aiding and diagnosis, and then the way in which the test might be used subsequent to the diagnosis. Is one from the research perspective that we're studying carefully. So that's something that I think you're gonna see a lot of additional data emerging in well conducted studies because we wanna make sure that before the company is giving a recommendation how to use these tests for tracking disease we really need solid clinical evidence. And C2N invests, very heavily into the evidence generation, because that's everything. It's the only way in which you build the trust of clinicians who are in the trenches and seeing these patients on a daily basis. And I think from our perspective, we have interesting publications that show we can use, particularly to your point, looking at. Not so much the APS two, the OID probability score two which gives you this zero to a hundred readout. But looking at the individual analyte measurements that are components of the APS or the IV 82 test in fact do have some interesting information they convey to people. So we've published multiple studies. In individuals that are asymptomatic, they have no evidence symptoms and on clinical exam would appear healthy. Maybe they have some risk factors for the disease, but cognitively normal. And it turns out some measurements can be Impactful for predicting who might be at risk of cognitive impairment years down the line. Or identifying people who have early pathology before symptoms have manifested today we don't offer the test for asymptomatic, preclinical use. However, we have a lot of ongoing studies. Publications that are starting to emerge to understand how we can best use these tools in preclinical Alzheimer's disease to help inform on risk management, aggressive lifestyle, behavioral modification, important data that just came out of the Alzheimer's Association International Conference in Toronto last week to show that lo and behold, if you apply. A fairly structured regimen of healthy lifestyle habits, exercise, healthy diet, better sleep patterns that all of these things can lead to delaying the onset of clinical Alzheimer's disease. That's a really profound observation that we can now prevent. We've been talking about prevention for cardiovascular disease for decades, and lo and behold, what's good for the heart is good for the brain. I think that you can imagine having these tools available in early people who are asymptomatic to help inform how to manage their risk factors or possibly even get therapies. Both Donanemab and Lecanemab are in clinical research, clinical development to understand if they can actually improve the clinical outcomes for people who don't yet have symptoms, and if you can delay symptom onset, then you're starting to change the trajectory of Alzheimer's disease The idea about tracking, there were two interesting publications One was the clarity AD study, the phase three study of Lecanemab now on the market. And the Trailblazer study, the Donanemab therapy, both studies used biomarkers the A beta 42 40 ratio in the LECAN study. We're able to demonstrate you can change that ratio. It normalizes effectively with treatment, people who respond to treatment. we see drops in the pTau 217 value with Donanemab treatment and even with Lecanemab, these markers might be useful for tracking disease progression. We don't offer a commercial product. to clinicians for clinical use, but you can imagine as an organization, and the evidence that we're starting to see come out of these big studies is saying there's likely something there. Let's further test and understand, as a test developer, we have multiple things to be thinking about. One is, regulatory oversight. We wanna make sure that we're providing clinical evidence to back. How our tests are used. We do have our test products offered under lab regulation overseen by CMS known as CLIA regulations. We also have our PrecivityAD2 tests. Is actually going to be submitted to the FDA, where the FDA would review that. And there will be a formal label around the use of that test, but it's consistent with a lot of the evidence that we've been generating. And then as a test developer thinking about, where's the field heading? You're already talking about where people are interested, they wanna track. This comes back to our earliest discussion, which is like, how can you use biomarkers? Today we're using the biomarker to diagnose. Aid in diagnosis tomorrow, we could be thinking about using it for tracking, disease progression or response to therapy or even using it to identify people at risk of future disease.

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Dr. Ken Sharlin: 33:23

And again, I want to be clear that our discussion from your perspective has to be very on label. What I may say is just an independent thought leader and clinician. But I've seen some really remarkable ways in which this has been helpful. I have one patient who has gone from positive to negative on the test and his journey started with making some lifestyle medicine changes and being very dedicated to that, to being randomized into the Envision study, which was Biogen's last gasp of Aducanumab before they decided to not pursue it from a business perspective, not necessarily from an efficacy perspective. But he had several doses of Aducanumab. And then I continued to work with this individual. And he happens to be a veteran. And I mentioned this because the VA system, has made these treatments available at least certainly. I think maybe the first one was LECAN was available. They can use Donanemab at clinician's discretion point being that as he and I worked together and used this test to track what was going on, I got to the point where I said, I don't really see where at this point giving you these drugs is. Change your outcome because you're already testing negative and what you're doing appears to be working. But the nice thing is I can test them every few months it allows me to do as an individual clinician is not only to say where are we at any given moment in time, but also to make clinical decisions. Okay, all of a sudden things are not going in the direction they were. Maybe we need to reevaluate. The use of, anti amyloid therapy.

Joel Braunstein: 35:08

We understand clinicians use the test suitable for their practice. Our label is for aiding diagnosis among people with cognitive concern. But as you also we've already discussed area of intense interest from a research point of view. And as more evidence comes out, as an organization, once we feel like we've reached a clinical evidence threshold to support having a commercial product and a message as to how to use these tests in those different applications, we would do but this is an ongoing r and d effort at C2N. That is very exciting'cause that's where the future of this field is heading.

Dr. Ken Sharlin: 35:48

This field of blood-based biomarkers for Alzheimer's disease is becoming increasingly crowded, There are other companies out there offering blood-based biomarker testing. And one, for example, incorporates Neurofilament light chain which is a non-specific biomarker of neurodegeneration. I have seen the P TAU 180 1 and clearly C2N has done the appropriate research and established the accuracy, predictability of the biomarkers that your company has chosen. But I'm wondering, if you can offer a broader perspective on this biomarker versus that biomarker.

Joel Braunstein: 36:30

Yeah, so I think we ultimately let the data speak for itself. So we're very evidence driven. I come from a strong research background. this company originated from Washington University School of Medicine and department of Neurology pioneers in trying to understand the basic biological mechanisms of Alzheimer's disease. And then trying to develop translational approaches to better treatment and diagnosis. And so I think that when you look at the core of C2N and what we represent, we really focus on what the data tells us. And so we have over 200 global collaborations where we're working with leading academic researchers clinicians like yourself in the community seeing patients provide realtime feedback from the use of tests in clinical care, and biopharmaceutical companies thinking about the next stage of therapy development. And so we take all of that data in-house. We use the evidence to tell us what is the most robust. Approach to clinical test design. And so from C2N's own experience, and I can't speak to the other companies out there offering different tests. we have a solid foundation to support the use of the Abeta 42 40 ratio and the pTau 217 ratio that we refer to in combining the algorithm. What happens is, you give a simple score report, right? that's the amyloid probability score Under the IV 82 test, we try not to overwhelm the clinician with a lot of information that could create extra noise. And so without specifying any specific analyte measurement, the more information you provide, the more potential exists for having discordant results between two markers and that we know can lead to more questions about what exactly is happening. So we design clinical tests in the most logical, and we use the term like parsimonious and robust model possible. And so parsimonious would say, let's throw in the measurements that we think are really driving the prediction of what it is we're trying to predict. We designed PrecivityAD2 to identify amyloid pathology. So when we look at multiple different approaches with many other variables, including some other analytes, we say, lo and behold, it's these two specific measurements. The A beta 42 40 ratio percent pTau 217, that are accounting for 95% of the output that we're trying to predict. So adding additional analytes comes at an expense, right? Expense in the form of potentially creating additional noise. That can potentially even impact the performance of your test. There's added cost, right? As the more measurements you're making generally drives up costs.'cause each test has its own, underlying costs. And so we try to focus on, where the evidence is telling us to go.

Dr. Ken Sharlin: 39:33

How do you envision the standard of care for Alzheimer's disease evolving the next 5 to 10 years? And what role do you think C2N is gonna play in that transformation?

Joel Braunstein: 39:43

I hope we're playing an important role. I feel good about our contributions today, C2N likes when we say what is it that's unique about C2N Diagnostics? I think we've been really leading innovators in the field and we've helped. Educate the global community with this new information. This is like really in the last five years is the only time that we had access to these blood tests. And you go to these big medical conferences and blood biomarker testing represents almost like 50% of the conversation We've been involved with many impactful studies as innovators we say what's next? Where's clinical medicine going? And we put that clinical lens to say, how do we design? What should we be focusing on? we see ourselves as innovators. We're gonna continue to offer new tests. About two weeks ago, we announced two new unique measurements that expand what we can understand about the tau protein and specifically trying to get to the other part of the pathology present in Alzheimer's disease tau tangles the audience has possibly heard about neurofibrillary tau tangles. a person who, undergoes an autopsy with Alzheimer's disease will have two pathological characteristics. amyloid plaques, and the other one is neurofibrillary tau tangles. And they're both integral to the disease process. It does appear that amyloid plaques precursors to tau pathology, but what we find with tau pathology is closely linked with clinical progression, when people display progressive memory loss, tau tangle pathology is really increasing. And so there's a huge clinical need emerging to understand not just amyloid pathology, but the other component of Alzheimer's disease. We've been developing unique assays that very specifically inform about tau pathology, and we think the combination is going to really continue to elevate the care. So we get into discussions starting with how are biomarkers used diagnosis today? But tomorrow we might be able to track clinical progression with these biomarkers. We might be able to predict who's at risk of converting from totally cognitively unimpaired to cognitive impairment in the next few years having those tools becomes essential to understanding the underlying biology of the disease. And so as innovators really trying to elevate the quality of the testing by being aggressive in publications, we think evidence really drives clinical adoption. And then C2N is also working on a very ambitious project where we are now starting to provide all our testing today in a core lab out of St. Louis, near Washington University. It's a private lab, it's the C2N lab and all of the samples that are done. Throughout the world are coming to C2N's lab where we make the measurements. But how can we address the global problem of Alzheimer's? it's not just a US-centric problem. You see the same concerns in Japan, Korea, Australia, Europe, uk, Canada, Brazil, all over the world to provide that solution with the high quality testing. We've been lining up partners that have major commercial presence in those specific regions, and we're building a platform system that will allow our tests to actually be performed locally. And so over the next few years, you're gonna see a lot more talked about for C2N as we expand into being able to address some of the global problems of Alzheimer's disease. And we wanna get into the personalized medicine approach. That we now use every day in cancer care is can we stage the disease? Can we determine whether there's other co pathologies like synuclein pathology common in Parkinson's disease? a lot of patients with Alzheimer's have mixed co pathologies, and those co pathologies can actually impact the appropriate treatment or how a person responds to treatment. So those are things we're working on.

Dr. Ken Sharlin: 43:58

As we're rounding up this interview, I want to throw something in that's for clarity's sake, purely speculation and research. It's not an on-label, if you will, application, but this is very common in the day-to-day practice of medicine. So I want to use an analogy and that is in the arena of multiple sclerosis. We now have 27 or 28 or so different disease modifying therapies, and they come from a variety of pharmaceutical companies have invested heavily in developing and having these treatments go through the appropriate regulatory process for approval. Point being they also probably don't sit around and have armchair discussions about how can we copy or how can we compete against our partners. Mostly they're focused on developing a unique molecule or product. at the other end of the spectra is what, when you have all of these treatments available. The clinicians are often faced with questions like, how do I choose, how do I recommend, Ocrelizumab versus Natalizumab versus, Ponesimod or what have you and there are post-processing rationalizations, meaning it's like some, it's an afterthought about how do we maybe line up these treatments, So now segueing into Alzheimer's disease, we have two anti amyloid therapies, monoclonal antibodies have been approved by the FDA Donanemab and Lecanemab, also called Kisunla and Leqembi. And on the surface they have the same indication, mild cognitive impairment due to Alzheimer's disease or early stage Alzheimer's disease. But when you dig into the actual mechanism of how these antibodies actually work, they're quite remarkably different in a sense. Because Lecanemab appears to target what are called the profis, the early evolution of the amyloid plaque, whereas DAB really just targets those mature amyloid plaques. Now, if somebody, it's getting Donanemab. There is a finite number of infusions 18 months, monthly infusion, and then they're done. And there is really no data that even says, Hey, if that person starts to accumulate, mature amyloid plaques and we restart this drug, there's no guidelines through, CMS or FDA and so any of that type of use would be definitely off label with Aducanumab. It does not target mature plaques. its effect, at the neuropathological level is more gradual. But on the other hand, it does ultimately reduce those mature plaques. It reduces those proto fibrils, which are very toxic with Lecanemab, there is no definitive endpoint, meaning it is possible to go into maintenance therapy after 18 months. this is contingent in my opinion, on where the neuropathology is to begin with, there's something called bra staging that looks at the evolution of the tau protein as it moves through the brain. And then there is also, it's out there. It's not as maybe widely accepted or established, but there's a way. To look at the same sort of staging, but ask the same questions in regard to amyloid. And my point here is that I believe that it could be possible, again, this is just research and speculation use these blood-based biomarkers to predict amyloid based bra staging. using that information to say, this person is more appropriate for Lecanemab and this person might be more appropriate for Donanemab, not telling people to go out and do this, but it has been on my mind lately as the person, we as clinicians, we're ultimately in the driver's seat, right? We have to make a recommendation to our patient and, it'd be easy to say. One's a every two week infusion and one's a once a month infusion. Who would wanna get an IV infusion every two weeks? But in reality, we had to think more practically there are individuals, I will see them with very subtle cognitive impairment. They're actually still pretty independent. They're doing quite well. They do have it may, they're a POE four positive. There's no question that they have the neuropathological changes, but I want to recommend the right treatment at the right time. And I'm just, again, pure speculation, but wondering if you have any thoughts about where such biomarkers might play a role in making those decisions.

Joel Braunstein: 48:34

Yeah, as the evidence emerges there's a, like a tremendous amount of research going on of which we're involved with a number of these big studies. You're exactly right. The definition of precision medicine is, defining the right patient at the right time with the right therapy and the pathway to a true precision medicine approach. Unfortunately doesn't lie in the clinical evaluation because it's just, it's too crude of a tool to really be able to make that specific decision. You can to some degree, but you really start to get into understanding where this person is on the biological spectrum of the disease, the amount of co pathology, the degree of tau, or tau protein in the brain. And all those indicators are really made possible through biomarkers. And so that is the future already being used in a number of research studies where people are using specific measurements. Some of the new tau protein measurements introduced for research use will find their way into clinical care once we have adequate data those tests guide treatment selection and treatment decisions. So I think it's extremely exciting. And the one other point you asked me about, where we're gonna be in the next five to 10 years, I think Alzheimer's is rapidly moving towards a preventable disease. Being able to reverse it, no evidence yet But slowing progression clear evidence. And the data as we move towards earlier stage, meaning people who are developing these markers 10 years before symptoms, we say, what can we do before the clinical impairment occurs, which is really what we're trying to prevent. It's the same thing. The analogy is like trying to treat high cholesterol before a person has a heart attack. this prevention model is going to absolutely be predicated because a person doesn't have clinical signs or symptoms. You have to rely on these biomarkers. That to me is a super exciting area because that's when you're really going to change the trajectory of Alzheimer's disease. For us to be able to talk, revisit one another, have this, webcast in a couple of years and say, Alzheimer's disease is a preventable disease now, to a certain degree. That's extremely exciting. I don't feel like there's many areas of medicine as exciting as today for Alzheimer's disease as to all the research piling in. And we know a lot more about this disease because of these biomarkers more sophisticated tools and drug design to say, when can we intervene? I do believe this will turn into a preventable disease.

Dr. Ken Sharlin: 51:10

I completely agree, as a clinician in the trenches, part of prevention is behavioral change, and this gets more into psychology, trans theoretical model and things like that of why people do what they do. There's a big difference between having an awareness of a change. Although for some people that's enough because they, maybe they have a family history, but suddenly when people realize. Those changes are present, even if they're in that bridge between preclinical and clinical. That's a powerful piece of information to adopt lifestyle changes. That, again, I think you were referencing the Wake Forest study recently published, but there are other folks out there, that have shown that, outside of even drugs, making changes in nutrition, optimizing sleep a medical therapeutic exercise program does make a huge difference. We're not necessarily curing the disease. But slowing the disease, yes. Seeing disease stabilization. In my personal experience, improvements in the amyloid probability score in the individual biomarkers. Yes. And then going from positive to negative in my own personal experience. Yes. So it's terribly exciting and I'm so honored to have had you on the Healthy Brain Tool Loss podcast today. Folks, again, this is Dr. Joel Braunstein, CEO and co-founder of C2N Diagnostics. This is Precision Medicine, which really defines 21st century medicine in inside and outside of neurological disease. So if you are not with a provider who's utilizing precision medicine tools, I would just advise you to make sure that you're connecting with the right people, the tools are there. And I love what you said about, Alzheimer's preventable because I'm sure you've seen this and not to, knock any organization up until perhaps fairly recently, even though Alzheimer's Association had a tagline, more or less saying, the disease without a cure, the disease, without a treatment. And I understand the drive behind promoting that sort of concept. And it does attract investment. It does attract, investment research dollars, things like that. But on the other hand, we have to balance that out with the fact that evidence-based medicine, tell us now that there are things that you can do for your brain, just like for your heart. thank you for being part of the podcast today.

Joel Braunstein: 53:38

Thanks so much Dr. Sharlin. Appreciate the terrific conversation.

COMMERCIAL BREAK: 53:45

Hi everyone. Dr. Ken Sharlin here with the Healthy Brain Toolbox. I'd love to hear from you. If you have general questions about brain health, neurology, or the science of keeping your brain sharp. Send them to questions@healthybraintoolbox.com. I'll be reading your questions on the upcoming episodes. Please remember, these need to be general questions, can't answer personal medical questions, or provide individual medical advice. So if you've ever wondered about brain health strategies, lifestyle tips, new research, or the future of neuroscience, send those questions in. I look forward to hearing from you and who knows? You might even hear your question featured on the show. Thank you for tuning into the Healthy Brain Toolbox podcast. I hope today's conversation gave you new insights to protect and nourish your brain. Be sure to subscribe, leave a review and share this episode with anyone looking to take control of their health. Until next time, stay sharp and keep learning.