p-Tau 217: The Breakthrough Biomarker Revolutionizing Early Alzheimer’s Detection

Join me for a fascinating conversation around an exciting breakthrough in dementia detection that’s offering real hope for early intervention. Dr. Hans Frykman, Chief Scientific Officer at Neurocode Laboratories, is here to share groundbreaking insights into cutting-edge biomarkers that can identify pathology associated with Alzheimer’s disease before symptoms even appear. What’s even more fascinating is how these same tools are revealing neuroinflammation caused by infections, including COVID, Lyme disease, and mold exposure—issues that are incredibly relevant in functional medicine today. The assays Dr. Frykman and his team have developed, and continue to research, are transforming the way we think about diagnosing and addressing neurodegeneration. We’re talking about a potential game-changer that allows us to intervene earlier, reverse damage, and ultimately improve the trajectory of these conditions. This is an extraordinary time in science and medicine, and the work we’re discussing today is at the forefront of it all. Don’t miss out on how this could reshape your practice. ~DrKF

p-Tau 217: The Breakthrough Biomarker Revolutionizing Early Alzheimer’s Detection

In this episode, Dr. Hans Frykman shares groundbreaking insights into p-Tau 217, the first blood test to detect Alzheimer’s-related amyloid pathology before symptoms appear. Alongside GFAP and Nf-L, these biomarkers offer a comprehensive view of brain health, tracking both amyloid pathology and neuroinflammation from conditions like long COVID and brain injury.

Discover how these tests enable personalized care, guiding treatment with lifestyle changes or drugs like Lecanemab and Donanemab. Early detection means better outcomes, and we explore when and how to incorporate these tests into clinical practice for proactive, tailored interventions. This revolutionary approach is reshaping Alzheimer’s care and improving patient outcomes.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald: Hi everybody, welcome to New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine. And of course, today is no exception. If you’re with us on YouTube, you can see that I am sitting next to Dr. Hans Frykman. Let me give you his background and we will jump right into what will be one of the most important podcasts, perhaps of all time, on my show. Dr. Frykman is CEO and Medical Director at BC Neuroimmunology Lab and Chief Scientific Officer at Neurocode Laboratory. BC Neuroimmunology Lab has a 35-year history of developing highly specific clinical neuroimmunology testing to the North American marketplace. The lab is a tech leader and is academically collaborating with several leading centers in Europe and the US, and we’ll be sure to talk about some of the research they’re publishing. Neurocode Laboratory is Canada’s first and only clinical whole exome sequencing facility.

Dr. Kara Fitzgerald: Dr. Frykman is clinical assistant professor of medicine at the University of British Columbia. In his background, he received his postgraduate medical training at Karolinska University Hospital, Mayo Clinic, University of Minnesota, Memorial Sloan Kettering and University of British Columbia. He’s got his medical degree from Karolinska Institute, bioorganic chemistry from the Royal Institute of Technology in Stockholm and a MSc in chemical engineering from Chalmers University of Technology. You went to school for a long time Dr. Frykman.

Dr. Hans Frykman: Yes, haven’t we all as physicians. It’s just lots of learning. Thanks so much for having me on, Kara. I really appreciate that. And also thanks for the introduction. I just wanted to point out that I am the Chief Scientific Officer of Neurocode Labs, which is located in Bellingham, Washington. It’s a very beautiful spot. Everybody told us that we’re not supposed to start any high tech company in a small city like Bellingham, and not in Washington. We should be in California and close to San Francisco and such, but we are trying to prove them wrong and I think so far, so good.

Dr. Kara Fitzgerald: Awesome. Yeah, it is a beautiful, beautiful part of the world. So the reason that I reached out to you— and we’ve had a couple of great conversations. You came and taught us on our clinical rounds— is that you guys, your team has developed three proteins. You guys have worked really hard on developing the assays around p-Tau 217, GFAP, which is glial fribillary acidic protein, and neurofilament light (Nf-L). You’ve been developing the technology that is incredibly sensitive and we’re going to be spending our time talking about why we need to be thinking about these as clinicians. There’s also plenty of savvy, regular folks listening to this who will be very interested in it. So talk to me about just an overview of these proteins and how you got interested in them and then we’re going to move through all three of them and we’ll start with p-Tau 217.

Dr. Hans Frykman: Yeah, yeah, that’s good. Thank you. So these are proteins that we can measure in blood, particularly p-Tau 217 is a very, very low abundance protein that we measure in extremely small quantities. We have to have very specialized equipment to do that and it is rather difficult. The other proteins, the Nf-L and the GFAP proteins, are both quite low abundance as well and we also use specialized equipment there. The utility of these proteins is that the p-Tau 217 is a very, very accurate protein reflecting amyloid status of the brain, meaning that if you have a misfolded protein, amyloid protein, that leads to Alzheimer’s in most cases down the road, and this can be picked up by doing this blood test. When it comes to Nf-L and GFAP, Nf-L measures something more related to really severe damage to the brain. For example, if you go with Jeff Bezos or Elon Musk’s rockets out in space, you damage your brain quite a bit. For those people that come back to Earth, we can measure quite a bit of increase in Nf-L because their brains are now damaged. That’s the reason why astronauts are only allowed to go on one trip.

Dr. Kara Fitzgerald: Wow.

Dr. Hans Frykman: Yeah, humans are not made to go in space, unfortunately.

Dr. Kara Fitzgerald: Well listen, since you took that little bit of a left turn, it’s really interesting, how long do you see Nf-L elevated?

Dr. Hans Frykman: It doesn’t go back to baseline because the brain is actually permanently damaged. Most of the astronauts, including people that worked in the space station, et cetera, they have problems throughout life afterwards. It’s quite a big sacrifice. We should thank them for that. It’s something that people don’t really know. But anyway, let’s get back to the main. Nf-L is kind of a non-specific protein that we can measure any kind of nerve damage in the periphery, but also in the brain. And then GFAP, the last protein, is perhaps one of the best proteins to measure all kinds of dementia, not only Alzheimer’s, but other types of dementia and it can be found very early. There are some studies that indicate that although it’s still early work. The other utility is that GFAP may also reflect inflammation in the brain and we have had, for example, COVID or other such viruses and…

Dr. Kara Fitzgerald: Lyme, neuroborreliosis.

Dr. Hans Frykman: Yeah, exactly. Other microorganisms, other inflammatory chemicals as well, mold, etc., can then increase GFAP. So this is something that is very useful to measure from that perspective. Definitely, we don’t want to have elevated GFAP for a long time, although it can happen occasionally that we have a spike. The three proteins then, in combination, make a very comprehensive view of the brain at any given time and then if you measure them longitudinally, you can follow what’s going on in your brain. They stay kind of the same for any individual person over time, although they may rise a little bit when it comes to, for example, p-Tau 217. It’s a very slow rise, but if something starts changing in the brain, then we’ll have a spike up and that will reflect that something more sinister is going on.

Dr. Kara Fitzgerald: So these can capture a wide variety of neuroinflammatory conditions triggered by many different causes, from traumatic brain injury to the pathogenesis of Alzheimer’s.

Dr. Hans Frykman: Correct, yeah.

Dr. Kara Fitzgerald: I was actually reading that in autism in some cases, we might see a rise in GFAP. I mean, there’s quite a bit of utility.

Dr. Hans Frykman:  Right, so the GFAP and Nf-L are unspecific. There are quite a broad range of different conditions where they can rise and so it kind of gives us an insight that we should investigate further. P-Tau 217 is highly specific just for amyloid really, and very, very few other false positive or false signals for other things.

Dr. Kara Fitzgerald: I’ve got a lot of questions, like when do we get them? But before you get into that, let’s just talk about p-Tau 217. How early might we see this close to or falling out of the reference range?

Dr. Hans Frykman: That’s a good question. With today’s assays, we are probably able to start seeing the signal with fair confidence already at the MCI stage. That’s the prestage of mild dementia— minimal cognitive impairment, it’s called— and that’s when you have some history of forgetting things and you have some history of not being able to execute things, but you’re still fairly functional, you live independently and so forth. That is a very good stage to be able to catch the disease, but obviously we’d like to do it even earlier. There will be second generation test that we will launch actually this year that will be able to even look at people that are cognitively unimpaired, meaning that they’re completely normal.

Dr. Hans Frykman: We can then differentiate with high certainty people that are cognitively unimpaired from those that are also cognitively unimpaired, but one has amyloid and one does not. And obviously for the ones with amyloid, the question becomes are they all going to develop Alzheimer’s? That’s something we do not know, but if they have genetic expression of even one APOE4 gene, then they are bound to develop Alzheimer’s. If they don’t have any APOE4, they just have APOE e3/e3 or other combinations, then we are perhaps looking at them more as a red flag. We’re not certain if they’re going to develop Alzheimer’s or not at this time.

Dr. Kara Fitzgerald: I want to circle back and talk more about the APOE4. There’s definitely people listening to this who have it and I want to get a little bit more clarification on that. But before I do that, what is this new assay? Is it just a more sensitive p-Tau 217?

Dr. Hans Frykman: Yeah, it’s 10 times better than the previous ones. We are the only lab in the US that has a very sensitive assay that can distinguish minimal cognitive impairment from those that do not have it with amyloid pathology. So if you go to the legacy labs such as LabCorp, Quest, or Mayo, they use an assay that is only useful in mild dementia. Our assay and their assay are the same in mild dementia, but our assay and their assay are different when it comes to minimal cognitive impairment.

Dr. Kara Fitzgerald: So they just have to be further along the pathology for LabCorp and Quest to pick them up.

Dr. Hans Frykman: If they’re further along the pathology any assay works, but if they are at the MCI stage, which is the best stage that we can catch at this time, then they should use our assay. If they want to even go further and detect it when they’re cognitively unimpaired, meaning that they were in a completely normal state, they have no idea what is going on in the brain, then our new assay is going to be the most appropriate test. So essentially, we can look at three different types of assays for different times in the pathology, if that makes sense.

Dr. Kara Fitzgerald: Okay. Sure, it makes total sense. But in the arena of prevention, where many of us in functional medicine sit, we’re going to be wanting to use the current assay and then the more sensitive assay when it’s available. I think most of us will just jump to the more sensitive assay. That makes a lot of sense.

Dr. Hans Frykman: Yeah. Correct, yes.

Dr. Kara Fitzgerald: So I want to push back— Go ahead, you were going to say something?

Dr. Hans Frykman: Yeah, I mean, it’s important that you then help the patients to understand what is their risk to develop things and also help them to feel comfortable with the plan and how to avoid getting Alzheimer’s. I think that it’s now possible to circumvent it.

Dr. Kara Fitzgerald: Yes. Yes, well I want to underline that and exclamation point that because when we were talking about the APOE4 folks, you know, I think we do have a choice in whether that leads to dementia at this point in the game. Would you agree? I mean I think Bredesen and other people are really putting some evidence behind the fact that we have a choice in outcomes, regardless of our genotypes.

Dr. Hans Frykman: Yeah, the data Dr. Bredesen shared with me is looking very promising. The people that have followed his protocol that are APOE4 have not developed dementia even at old age, which in normal cases, almost 100% developed dementia by the age of 70 or 75.

Dr. Kara Fitzgerald: It’s extraordinary. It’s just extraordinary.

Dr. Hans Frykman: So it’s backwards. You can prove it backwards. Essentially, if you have APOE4/4, you’re supposed to develop dementia at a certain age. If you don’t, then it’s remarkable.

Dr. Kara Fitzgerald: It’s absolutely remarkable. Yeah. So this is Dale Bredesen. Folks, we’ll just link in the show notes to anything that we’re referencing here, papers or otherwise and my conversations with Dr. Bredesen we’ll make available to you as well. The Bredesen Protocol, if you’re not familiar with it, is just one of the most extraordinary programs out there. But also, just on this track, you’re involved in some, I think, some drug trials. People are using your assays as well. Is there anything promising in that arena?

Dr. Hans Frykman: Yeah, I think there are certain drugs already now coming to market in many countries. The United States was, I believe, the first country to launch Lecanuemab and Donanemab from Eisai and Eli Lilly. Those drugs work very well in some patients with even reversing cognitive decline. They have gotten a stamp that they’re not fantastic drugs, and that may be true in that they don’t help every one, but at the same time there are people, and I’m getting feedback constantly now, that there are people that are completely kind of reversing. So it’s depends. Is your belief in the methodologies of Dr. Bredesen or if you believe in hardcore pharmaceutical treatments or both, or either, you’re starting to have choices here, is what my point is.

Dr. Kara Fitzgerald: Yeah. Do we know who is more likely to respond to those?

Dr. Hans Frykman: Yeah, I think the ones that have pure amyloid pathology, which we measure with our assay, those are the ones that are more likely to get benefit, and earlier on in the disease process. It takes time for these drugs to work. However, those that don’t have APOE4/4 are probably better off using these drugs than the ones that have APOE4/4 because the drugs can be dangerous for that group with brain bleed that leads to ARIA, (amyloid-related imaging abnormalities ), which is brain swelling, and then neurodegeneration, which is actually worse. Those people can come out even worse than they were originally. This is the warning for those drugs and there’s been lots of work going on on how to avoid that. Some centers, like Johns Hopkins for example, are not admitting APOE4/4 at this time because of the high risk to those patients. With that in mind, I think having all the information you can make an informed decision.

Dr. Hans Frykman: I think for the first time as a humanity we’re addressing this with the brain more seriously. And as always, when you open the door and start really exploring this and going deeper, lots of different options starts to appear. I think we’re just in the beginning of what is happening here. It’s quite a revolution. So we’ve gone in very few years from not being able to do anything to being able to really help many people.

Dr. Kara Fitzgerald: Yeah. Diagnosing earlier and earlier and perhaps some medical interventions that can make a difference in a subpopulation. And then we have the Bredesen protocol and I think that Bredesen has already reported— I know they haven’t published on it yet, but they’ve got an ongoing trial that people can access at clinicaltrials.gov. They’re measuring all three of your markers and they’re seeing favorable turnaround in those markers, correct?

Dr. Hans Frykman: Yes, they are. Yeah. The evidence is likely going to be published sometime later this year or early next year. I think the conclusion of the trial is late this year. I think it’s a larger trial than he did last time. They have much more powerful biomarkers than any other such trial has had and in our case, we have done a very, very large validation on these biomarkers, particularly p-Tau 217. We did a comparison with 1,700 different well-characterized samples. The first thing you have to do is to measure people that are completely cognitively normal and we did that with an Australian collaborator, called the Able Consortium in Australia. They have a large number of patients that have had PET scans that are normal. The patients are normal and they’re cognitively normal and so with that material, then we can plot the normal curve and with that in mind we are then able to be very sure of our cutoffs. When is a person having amyloid and when they do not have amyloid? Nobody else in the world has done anything like we have in this regard. That’s why our assay is really the only one that you can use in the earlier settings of memory problems.

Dr. Kara Fitzgerald: And I want to commend you because I know that it was really difficult getting those samples and that it was a great cost financially. I think just technically manifesting this body of work that you’ve done is really pretty revolutionary for the field. So thank you for that.

Dr. Hans Frykman: Yeah, thanks. It’s been very rewarding, I think. You could do all the science work you want, but then at some point you have to go out there and try your thing to see if it’s going to really fly or float. And for us, we did that and it is and we get really good response. We were chosen for the three, I would say, prospective trials with Michelle Mielke who is a younger star, full professor at Wake Forest. She was a professor at Mayo Clinic previously. She has one study in the primary care where they compare our test with PET scans and the first number of tests, in the first weeks we were on 100% correlation with the PET scans. This was something prospective, you know, it’s very hard to correct afterwards, right? It’s ongoing and real-time use of your assay because we did this very, very large work initially to really get the cutoffs correct and know a lot about our assay, we were able to provide it in a prospective setting, meaning in real time. We have three such trials going on with the University of Texas at Austin, as well as UPMC, which is University of Pittsburgh Medical Center.

Dr. Kara Fitzgerald: How did you then improve on the assay? How did you improve the ability to detect at such… What is it, pico? What are you measuring it at?

Dr. Hans Frykman: Yeah, it’s just the same picogram per milliliter kind of thing, but the improvement is really in the antibodies. The antibodies that we use are better. It’s always like that to humans. First you come out with something, it’s amazing, but then you realize that even that amazing result can also be improved on. I can take the resemblance of troponin, for example. When troponin came out, the guy was from Germany and he was ridiculed for many years, but eventually troponin came through and it’s the blood test that is so useful when people come in and say, I have a heart attack. You get troponin drawn in the hospital and then they observe you and then you get another troponin drawn. And if both of them are negative they send you home and there’s almost nobody that dies from heart attack at home, which used to be very, very common. They sent the wrong patients home in the old days. So troponin has been revolutionary and today we’re on the sixth iteration of troponin, right?

Dr. Hans Frykman: In the same way, we’re probably going to be on many iterations of p-Tau 217 because it’s one of those amazing assays that come around very, very seldom, probably every 20 years, as it’s so, so accurate. I think the last time that this happened was actually troponin, which happened about 20, 25 years ago.

Dr. Kara Fitzgerald: But the legacy labs, have they developed their own technology and it’s less sensitive and it’s really… Other than later stage, it’s just not going to be useful.

Dr. Hans Frykman: Yeah, they don’t really show much passion behind this, or knowledge. It’s a bit surprising to me that they didn’t put more effort on this, honestly. But they have the distribution and obviously the practitioners that want to use us have to work a little bit harder. Our assay is a bit more expensive, you know, things like that, but it definitely is going to be worth it. If you want to take the test, you might as well take the best test.

Dr. Kara Fitzgerald: Yeah. Are you guys getting insurance coverage? Where are you at on that journey?

Dr. Hans Frykman: Yeah, I think we’re probably getting that in 2025.

Dr. Kara Fitzgerald: Alright, so talk to me about the different p-Taus. I mean, if you go into the literature, you see that p-Tau 181 is being used. Why 217? How do we think about the different p-Tau proteins?

Dr. Hans Frykman: Yeah, that’s a good question. We don’t know really why. They’re just phosphorylated on certain sites of the tau protein, but p-Tau 181 is much more abundant. It was the original blood-based assay that came out in 2020 for the first time. That was a really good assay. Actually the first work was done by Michelle Mielke, the person I mentioned earlier, already back in 2017, but a really good assay came in 2020. However, it was already known at that time that 217 probably has a better signal-to-noise ratio than 181, so the experience with 181 was more comprehensive. But 217 has emerged because it has a better signal-to-noise ratio. We’re more certain that we are measuring the right thing and that we’re identifying the right patients. However, with the 217, it is difficult to measure it and there’s only a few instruments that can do it properly. We have many specialized equipment in our lab that can measure this and we have the instrument that is used by the legacy labs as well, so if anybody wants that, we can offer that at a much cheaper price than them. We’re not necessarily talking against that assay, but we’re just saying that if you want the best, especially early on in disease, you should definitely ask for the ALZpath Dx. It is the current market standard.

Dr. Hans Frykman: We have a new paper describing how good that assay is. In that paper, we used neuropathology samples. Neuropathology is the ultimate gold standard for measuring this amyloid pathology, and in that we found that the ALZpath assay was far more sensitive, actually, than the Lumipulse assay, which is the assay that the other labs have chosen as their main assay. We have chosen the ALZpath assay as our main assay, but we’re also able to report the Lumipulse assay. If people want us to measure it through that assay, we can do it as well.

Dr. Kara Fitzgerald: Okay, okay. And then just for anybody who’s familiar with some of these biomarkers, Quest has a Plasma Beta-Amyloid 42/40 Ratio that I know you’re not a fan of. Can you just speak to what that is just briefly, because we’ve got other stuff to cover, but just in case it’s on anybody’s mind.

Dr. Hans Frykman: Yeah, that’s a good idea. Yeah. So, Aβ42/40 was the FDA approved assay in CSF, that’s spinal fluid, and it’s a really good assay in spinal fluid. However, it does not work in blood because there’s peripheral production. What that means, in this case, the Aβ42/40 decreases. So it decreases, it’s not a normal biomarker where the biomarker goes up, which is also the case of p-Tau 217 and 181, those go up. This biomarker decreases. But at the same time you have the body producing Aβ42 outside and then if you measure it in the bloodstream, this is confounding the results. What we have there is a very, very, very small difference, less than 10%, between pathology and non-pathology, which is within their margin. So essentially, if you get a positive result there, it might as well be something that is completely normal. Therefore—

Dr. Kara Fitzgerald: So it could be just peripheral beta.

Dr. Hans Frykman: Yeah, Fujirebio has decided that the FDA approved assay should be p-Tau 217 through Aβ42. While we like the Fujirebio assay for mild dementia, as I mentioned, we don’t like it so much for MCI, but we like it for mild dementia. We do not necessarily concur with Aβ42 being in the mix because it just increases the uncertainty. But that’s more of a statistical analysis discussion. I don’t think it’s something we’ve gone into here, but in general, I would say that the p-Tau 217 is a very, very strong biomarker, and we use that by itself. There’s no need for other biomarkers if you want to detect amyloid. There are other proteins in the brain that can be misfolded that are important to detect and we don’t necessarily have the right methods developed yet, but in the future we will be able to detect many different proteins even through blood, particularly through CSF.

Dr. Kara Fitzgerald: Just name one that’s coming down the pike in blood that you’ve got your eyes on.

Dr. Hans Frykman: Yeah, in blood we have something called BD-Tau, which is the total tau that is developed in the brain, so brain-derived tau. That protein can be useful to measure in stroke, in rapidly progressive dementias, such as Creutzfeldt-Jakob disease, you know, very sinister things. This is a protein that can give differentiation, so If you measure p-Tau 217 and you measure BD-Tau at the same time, if they’re both elevated, then it points to amyloid disease. If p-Tau 217 is normal and BD-Tau is elevated, then it points to something else. It gives you a signal that something else is going on and probably something that is quite a bit more sinister than just amyloid.

Dr. Kara Fitzgerald: Okay, and when will that be available?

Dr. Hans Frykman: Yeah, it will be available in 2025 also. And then we are developing other biomarkers. We have a new biomarker in CSF, so in spinal fluid, that’s called MTBR or tau 243. This is a biomarker that is actually already in the protocol from the Alzheimer’s Association, the NIH, and the NIA, which is the National Institute of Aging, for detecting neurodegeneration and that measures tau that relates to Alzheimer’s. So in Alzheimer’s, it’s a dual prognopathy. First, you will see amyloid formation, and then that eventually triggers a certain kind of tau pathology, and this biomarker is supposedly, although it’s early days, able to detect that tau pathology.

Dr. Kara Fitzgerald: Okay. Alright.

Dr. Hans Frykman: So, that’s one of the hot biomarkers. But I think there’s nothing in the pipe like p-Tau 217. That’s just a home run for us as a medical community to be the first time ever to have such an accurate blood test.

Dr. Kara Fitzgerald: Yeah, yeah, yeah. Everybody who’s listening, clinicians, information about the lab, the papers that have been referenced thus far, all of that will be docked over there in the show notes. And also just for regular people or people who want to get this suite of testing that we’re talking about, we’ll put information on the show notes for you as well. All right, so when do we want to start doing this? When do we want to get a p-Tau? And if it’s within normal limits, if we have APOE4 or APOE4/4, if we’re homo- or heterohomozygous, what’s the frequency that we’re going to be looking at this? What age do we start at? And then if we’re APOE3/3, same question. How do we use this clinically in a prevention context?

Dr. Hans Frykman: That’s a great question. I think it’s up to everybody to decide, right? We now have the possibility to detect this early, and perhaps really early is what we’re seeing. And now I’ve been sitting here promising that we’re going to have something really, really good this year. We have something that is already very good, but we’re going to have something even much better. Now, obviously as you sort of bend up the eye, you can put in and say, okay, now I can start seeing things and maybe it’s too much information for some people, right? And they are walking around with this amyloid in their brain and they feel fine. That may be something that makes people depressed or, you know, it’s not something that they want to know. So I think it’s up to everybody.

Dr. Hans Frykman: But I would say it’s like detecting cancer in stage one or stage zero. Wouldn’t you like to detect cancer in stage one or stage zero? The answer to that question is probably yes for lots of people, but not for everybody. I know people that worked with clinical chemistry their whole life and didn’t take the tests that indicate prostate cancer, for example. There could be all kinds of reasons that people just avoid taking a test, and I’m not here to judge that. I think it becomes a very personal question, but this is starting to be available for those that are curious, that are interested to be proactive. This is who we are turning to. And others that don’t want that or for other reasons are not interested, that’s fine as well.

Dr. Kara Fitzgerald: Yeah, I think that’s fair. What age do we want to look at this? Like if we’re APOE4 or 4/4, let’s say, or 4 with a family history and we have the guts to go in and look.

Dr. Hans Frykman: Yeah. I would probably start at 50.

Dr. Kara Fitzgerald: Okay.

Dr. Hans Frykman: So there are earlier dementias such as presenilin and such, but those are developing already in their 20s. There are other types of dementias also, or it can be related to microorganisms that can develop earlier, and the overlapping without a disease such as ALS and such. So there are others where it’s earlier, but then it’s quite evident, right? But for somebody who’s cognitively normal and has APOE4/4, I would start at 50, personally.

Dr. Kara Fitzgerald: And what about 3/3, say, with family history or no family history?

Dr. Hans Frykman: So, yeah, personally I have 3/3 and I have some family history so I measure myself. Yeah. You know, that’s me, but I would say that nobody knows what… And it’s again, it depends on anybody’s preference.

Dr. Kara Fitzgerald: How frequently? Would this be an annual? I mean, I know it depends again on history and genetics.

Dr. Hans Frykman: Yeah, that’s right. I think annual is probably fine for some people, but I think every two years is also fine, I think, for some other people. It depends if it was elevated or it was completely normal. We have two cutoffs. We have a cutoff that shows that if you’re in that first category where it’s very low risk, then you can certainly wait two years. Nothing will happen in the two years or it will take two years before anything happens. And then you have intermediate cutoff. There I would suggest that you come back in six months. Then you’re intermediate risk. About 50% of those are actually positives, but we are very careful to name who is positive and negative at this time so we have an intermediate zone. And then we have a high zone with a high risk and those are actually positives. They are very, very highly likely with over 95% certainty that they have the amyloid pathology and they should go on to do something about it, and as I mentioned, there are many paths now to help yourself. Even in the study with Michelle Mielke, which is NIH funded, we have lifestyle changes for MCI, yes.

Dr. Kara Fitzgerald: Oh you do? Okay good. Good. Alright well we’ll link to that study.

Dr. Hans Frykman: So yes, Bredesen started this with the knowledge about what we could do and changes in our lifestyle and other things and he’s very comprehensive, but it’s seeping into mainstream as well now at this time.

Dr. Kara Fitzgerald: Fortunately.

Dr. Hans Frykman: It’s good to know. There are some people that are are not happy mentioning Dale Bredesen, but I think there’s lots of people that are starting to acknowledge that he was onto something, also.

Dr. Kara Fitzgerald: Yeah, it’s extraordinary work and a colleague and friend of mine, Heather Sandison, published another trial using his intervention with good outcome in MoCA scores (Montreal Cognitive Assessment) and other cognitive measures, which is exciting. But I know she didn’t use your assays, although I believe that will happen in the future. Final question on p-Tau, then I want to talk about the other two. For follow-ups. You’re doing an intervention, you’re following the Bredesen Protocol, you’re doing it really, really carefully, or you’ve decided to go the drug route, or you’re doing a combination, whatever. How early can you actually see a shift in p-Tau?

Dr. Hans Frykman: Yeah, that’s a good question. I think 3-6 months. It depends how aggressive you are and if you’re following all the ways. And for that matter, we can also use the new assay that we’ll have launched sometime mid-year in 2025. Even the ALZpath assay is able to measure that decrease to some degree, but with the new assay, because the range is going to be much, much bigger, we’ll be able to see even more of that change. And we’re quite excited for this new assay just because of that. So not only can we detect very, very early pathologies, but the change, the treatment effect, we’re going to be able to measure in a much more accurate manner, I think, using this new generation, second generation assay.

Dr. Kara Fitzgerald: So p-Tau 217 is really quite specific for Alzheimer’s, but then we get to GFAP (glial fribillary acidic protein) and Nf-L, and these guys really open the door. They might track with Alzheimer’s pathology, but you can see them in traumatic brain injury, in long COVID, as you mentioned, in neurolyme, neuroborreliosis. You can probably see it in MS.

Dr. Hans Frykman: Yeah, that’s correct,

Dr. Kara Fitzgerald: But you can see these maybe in acute inflammatory… Beyond COVID, other viral illnesses. So these guys really expand the utility of these analytes beyond solely zeroing in on Alzheimer’s. So talk about that.

Dr. Hans Frykman: Yeah, I think GFAP is the quick cousin of Nf-L, so to speak. If you want to be more aggressive… Nf-L came quite a few years ago, more than 10 years ago, and was first developed in Sweden. GFAP is a more recent development, just a few years ago. It’s particularly developed with the work of Charlotte Teunissen in Amsterdam. Initially it was thought that we’re going to be using it for Alzheimer’s, but that’s now been discarded. Instead it’s been thought that it is important to measure it in a number of different cases and can be used as a very— The uptick is very quick versus Nf-L. It takes a long time before we start seeing the uptick, so, for example, in brain injuries we see the uptick in just three days. It peaks out with GFAP, while Nf-L peaks out at day six or something like that.

Dr. Kara Fitzgerald: What kind of brain injury? Like mechanical or just any?

Dr. Hans Frykman: Traumatic brain injury or even other types of brain injuries. There are lots of different uses of GFAP that extend beyond that, particularly inflammatory situations where GFAP alone is rising quickly. And then we had this publication out of China early last year where they looked at a huge number of proteins and identified GFAP as perhaps one of the best early detection proteins for all types of dementia. There are many types of dementia out there. There’s the amyloid type, which then leads to Alzheimer’s. That’s around 60% of all the dementias where amyloid plays a role. But of all the Alzheimer’s, 50% are pure amyloid and 50% are mixed pathologies. If you take the pure amyloid of all dementias, it’s about 30%, and then another 30% is mixed pathologies and then around almost 40% have other types of pathologies and that can be a whole host of different things.

Dr. Hans Frykman: FTD (frontotemporal dementia) is one where a certain type of tau pathology leads to very sinister disease, you know, what Bruce Willis has. I think he became the poster person for that. It’s a horrid disease with personality changes and it’s something that’s very, very sad. We don’t know much how to interfere with those types of dementia yet. Then you have other types of dementia. You have TDP-43, (Transactive Response DNA-binding Protein 43), which is related to ALS. Many ALS patients have dementia as well. And then you have synuclein-related, which leads to Parkinson, but Parkinson also get dementia. Then you have vascular dementia, which often overlaps with some of the proteins as well and that can also be a pure dementia, the vascular dementia. So there are–

Dr. Kara Fitzgerald: And you’ll see GFAP in all of these presentations.

Dr. Hans Frykman: Supposedly, yes, according to that publication. It’s early work and as I said, this has not been validated further, but it was a very, very large study from China where they used an enormous amount of samples and different proteins. And it was all out of UK. They collaborated with the UK Biobank.

Dr. Kara Fitzgerald: Is this useful as something that we want to incorporate into our annual screenings?

Dr. Hans Frykman: I think so for the people that are more ambitious. Yeah. I think as we mentioned, p-Tau is a yes or no answer, while GFAP can open Pandora’s box more and can be more difficult to actually get something out of. So let’s picture a situation where you have a patient that is then normal on p-Tau 217, normal on Nf-L, but has a high GFAP. Are you supposed to be concerned? The answer is yes. You should probably go for a fishing trip to see what is going on. Do we have all the tools to get to the final conclusion? I would say that sometimes we do, sometimes we don’t. With that in mind, again, I think it’s a personal decision. Do I want to use everything that is available to me? But I also have to understand that if I get a positive GFAP, it’s possible that we don’t find any reason for it.

Dr. Hans Frykman: How can I then manage that? Well, there are lifestyle changes to address that and look deeper. Do you have chronic infections? Do you have mold in your house? Do you have heavy metals? There are lots of things that may be giving you problems and this could be an early indication. So, yeah, then you go back and look at all these things and everything comes out fine. Then, all right, then you go and do the best you can in your lifestyle and then you measure it again and hopefully that was just a blip on the screen and everything comes back to normal, right? It suits some people to use GFAP that way and some people don’t like to be worried about it. So it’s really a personal decision.

Dr. Kara Fitzgerald: I hear you. That makes sense. I mean, it could be that maybe they moved through COVID recently. You could cast a really wide net, I would imagine, with speculating. If somebody has a really high GFAP, are they likely to have symptoms or not necessarily? This individual we’re talking about probably doesn’t.

Dr. Hans Frykman: Not necessarily. We have seen cases where GFAP alone is elevated and I see that people are not 100% comfortable with that. At the same time, there are people that say, wow, that’s a new chance for me to address this and go deeper and if everything looks fine, then I’ll make all the other tests that I mentioned and you’re probably going to be OK. You just have to try to live as good as you can and then eventually it’s going to resolve. At least that’s my belief.

Dr. Hans Frykman: But again, we’re very, very new to this biomarker. So for GFAP, for example, I just want to go back to the lab. We did not have a good assay previously. We were the first lab in the world to set up a good GFAP assay and that is a quite recent occurrence. We have just had it available for six or seven months or so. Previous to that, there was an assay that wasn’t dependable. It wasn’t robust and so whatever we measured at that time wasn’t really correct. Now that we have a good assay we are exploring novel territory. It’s just what happens, right?

Dr. Kara Fitzgerald: What about inflammaging? I was talking to your medical liaison, Mike, who said that you’re going to have age-associated reference ranges super soon, very soon for GFAP, and inflammation is a phenomena that increases with aging, which has to have something to do with the reference range changes. It seems to me this could be another useful reason to get in there and to engage in lifestyle interventions. It’s my area of focus. It’s my bias that we have some say over how well we age and it seems like it might be a useful tool there. Do you have thoughts on that?

Dr. Hans Frykman: Yeah, I think so. We often think that we can abuse ourselves. What we forget is that the body can take more abuse than the brain and we come out with a short stick with the brain. People think oh, it’s so cool to do this and that, but at the end, if you don’t sleep, if you travel all the time, you know, let alone drink alcohol and smoke, which I’m thinking not many people do on this podcast, but even other habits such as looking at your iPhone at 10 PM and not sleeping well, all that is going to get to you and the brain. So I think we have to be careful with the brain. It’s still a very, very important organ and tool for us.

Dr. Kara Fitzgerald: Yeah, that’s right. I could see these assays being, as you said earlier, really scary for certain individuals. But also, they have the potential to be incredibly motivating. Laboratory data is powerful and to your point–

Dr. Hans Frykman: Yeah, it’s a whole new world. It’s a whole new world.

Dr. Kara Fitzgerald: Yeah, just being able to identify these changes early. All right, so let’s talk about neurofilament light (Nf-L). I mean, gosh, not that I’ve had the opportunity to be an astronaut, but I can’t say that I would be excited to go on to live with an elevated neurofilament light. This is similar to GFAP. So talk to me about this protein. I’m also curious, since you brought the astronauts up.

Dr. Hans Frykman: Yeah, GFAP is more brain specific. It’s related to inflammation, and can be related to other things going on in the brain. Also, it’s not only inflammation. It’s not highly specific for inflammation, but it is quite specific. Nf-L is really more like nerve damage anywhere in the body, so you can get increased Nf-L if you have nerve damage in your leg.

Dr. Kara Fitzgerald: Oh, interesting.

Dr. Hans Frykman: You can get increased Nf-L if you have a brain injury, obviously. So Nf-L is more like any nerve gets damaged, neurofilament light is released and the assay picks that up. This is an assay that has been around for quite a few years, as I mentioned, probably 10 years. We have really good assays for more than 10 years. The utility of that assay is multifold and it’s used in some centers a lot, some centers not so much. But it’s not specific for anything. It’s kind of… They say it’s troponin of the brain, but I feel that troponin is still fairly specific. Nf-L is less so. I think it’s more like CRP in an infection or something. You can just say that something was damaged, something is there. But it’s very general and it can be, as I said, quite a few different things. But if Nf-L is increased, then this is something that really draws our attention.

Dr. Kara Fitzgerald: What was the clinical outcome of the astronauts? What kind of symptoms did they experience post flight? I know you don’t want to talk about it, but I keep…

Dr. Hans Frykman: Yeah, they’re not as good as they were before.

Dr. Kara Fitzgerald: Not as cognitively sharp?

Dr. Hans Frykman: Well, everybody has different reserves, right? So I think it’s quite a bit of variability there, and depending how long they were out in space. I don’t imagine that the trips that Bezos and company do and those kind of shorter trips in the near atmosphere are very harmful, but definitely going to Mars or going to the space station or longer trips like that, they are quite damaging.

Dr. Kara Fitzgerald: What’s the mechanism that prompts the damage?

Dr. Hans Frykman: I don’t know. I think that this is just an environment that humans were not built for.

Dr. Kara Fitzgerald: Right. Can we change neurofilament light? If we get it can we do lifestyle interventions and actually improve upon it like we can the others?

Dr. Hans Frykman: Yeah, to some degree. I think that it’s like if you have a traumatic brain injury, depending on how severe it is. Can you reverse that? Yes, it depends on so many things. If you’re a young child, you know, most children that have a traumatic brain injury are able to do quite well in life. Not 100%, but maybe 90%, right? The older we are, the more it’s going to affect us and the harder it is to heal the brain. So the question depends on the severity. It depends on many things. What we do see is that it doesn’t go back to baseline, necessarily.

Dr. Kara Fitzgerald: We’re kind of coming to the end, but I just wanted to circle back to the fact that you see these markers track with clinical presentation. You’ve seen them track with imaging as well, both diagnosing a condition, but also as we can see some improvement. think Bredesen is working on that, tracking these markers alongside.

Dr. Hans Frykman: Yes, correct.

Dr. Kara Fitzgerald: I think he’s doing MRIs. I think he might be using BrainKey.

Dr. Hans Frykman: MRIs, yeah. An MRI is useful to, again, rule out that there’s other proteinopathies going on. If the brain is starting to shrink, that is either very late stage Alzheimer’s or it is some other more sinister proteinopathy. You can also see the vascular dementias on MRI. So, MRI is good to rule out other things, but if the brain looks kind of normal on the MRI and the p-Tau 217 is elevated, then it’s an even higher chance that you have Alzheimer’s.

Dr. Kara Fitzgerald: Well, Dr. Frykman, I just want to say it was great spending this last hour with you talking about these proteins. What incredible work you’re doing in just really moving the needle on our ability to detect and therefore develop effective therapies in the different dementias, but also beyond that on the different neuropathologies. So thanks for spending time with me and I just want to ask if there’s anything we missed here.

Dr. Hans Frykman: Yeah, thanks, Kara. Thanks for having me on. It really was a pleasure and great questions. I think anybody who has questions, I would like to encourage them to email me. I provided my personal email address and I’ll try to get to responding to as many as possible. I’m not sure how many people are on the podcast here, but obviously, these are new things. I don’t have answers to all the questions. We are dwelling into a new universe, in a way, which is a fascinating universe for us that work in it. At the same time, it’s important to get this right, I think, and to look after your brain, obviously. In the case of amyloid, I wanted to say that there are lots of opportunities now to take care of that or to help yourself, both preventive methods as well as ways to address it either by these protocols by Dale Bredesen or by other functional neurologists or by pharmaceutical agents or whatever suits you. So don’t hesitate to get this checked out. I think that is important to mention that we’re moving into a whole new era, right? We’re still early days, but we’re moving into a whole new era that is very, very positive for humans.

Dr. Kara Fitzgerald: I think that’s right. It’s a real extraordinary time to be practicing medicine. To be in medical sciences and in the practice of medicine. Yeah, there’s more hope than when I first started my career. All right, everything will be over on the show notes, folks. The citations, Dr. Frykman’s contact information, all of the information about the lab, so just head over to the show notes. And again, thanks so much.

Dr. Hans Frykman: Thank you. Thanks guys.

hfrykman@neurocode.com

Hans Frykman MD, Ph.D., FRCPC is the founder, CEO, and medical director of BC Neuroimmunology Lab located in the UBC hospital on the University of BC campus in Vancouver BC. He is the medical director for Lykke Lab a genetics laboratory also on the University of BC campus. Also, he is the CSO for Neurocode Lab Inc. in Bellingham WA, a high-complexity, specialty lab focused on neuroimmunology and biomarkers in neurodegeneration. Dr. Frykman has a clinical faculty position at the University of British Columbia, Faculty of Medicine, Division of Neurology.

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Dr. Dale Bredesen

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Study: Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

Research Article: Clinical decision points for two plasma p-tau217 laboratory developed tests in neuropathology confirmed samples

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Charlotte Teunissen, PhD

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Podcast: Tackling Alzheimer’s Disease Head On – the Inspiring Work of Dr. Heather Sandison

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