[00:00:12] Speaker A: Welcome to the Age of Aging, a show about living well with an aging brain, produced by the Penn Memory center and the Michael Nadoff Communications Hub. I'm Terence Casey and this is our annual special recounting the takeaways from the Alzheimer's Association International conference held this year in London.
Every year, Our executive producer, Dr. Jason Karlewish, sits down with colleagues fresh off the conference floor to talk through what stood out, what's changing and what it means for the field and for patients.
This year he's joined by Dr. David Wolk, co director of the Penn Memory center and co chair of this year's conference. And by first time guest of the show, Dr. Chris Brown, assistant professor at Penn and a clinician and researcher at the Penn Memory Center.
They cover a lot of ground from where biomarkers like P. Tau 217 stand today to how the two approved anti amyloid drugs are performing to what's coming next, including a new brain shuttle antibody from Roche and early results from a Biogen trial targeting Tau.
They take on the hard questions at the intersections of practice, policy and economics that the field is starting to face now that effective treatments exist.
Before we get into it, a reminder to subscribe to the Age of Aging wherever you get your podcasts. Season six drops in September and you won't want to miss it. Take it away, Jason.
[00:01:34] Speaker B: Welcome, Chris Brown. This is your first time on the Age of Aging podcast, right?
[00:01:38] Speaker C: It is, it is. It's very exciting.
[00:01:40] Speaker B: Yeah. Welcome aboard. Yeah, no, it's great to have you here and of course, always good to be back with my buddy Dave.
[00:01:48] Speaker D: Yeah, nice to be here as well. Return guest.
[00:01:51] Speaker B: And here is Philadelphia. We are in Philadelphia right now, speaking from our offices on the Penn campus and in the spirit of alone together, where our private office is linked by zoom, but on the same campus. One month ago we were in London, so I stayed on St. James Place area. Where'd you stay, Dave?
[00:02:11] Speaker D: I had the pleasure of staying near the conference center.
[00:02:14] Speaker B: Oh, how splendid.
[00:02:16] Speaker A: Yeah.
[00:02:18] Speaker D: Scenic of places as where you were.
[00:02:21] Speaker B: No, not at all, Chris.
[00:02:22] Speaker D: But convenience was good.
[00:02:24] Speaker C: Yeah, I was. I was by the convention center for the meeting, but I wisely stuck around and stayed down near the Kingston Garden area after the meeting. So I got a little bit of real London.
[00:02:35] Speaker B: Yeah, especially the unreal London of the. Of the Excel Center.
So, Dave, were you there in 2017? I know Chris wasn't because he was still in high school.
Uh, but this was a return, right, Dave? Yeah, yeah, yeah. So what, how did you think 2017 and 2026 differed other than nine years. The place was the same, by the way. But other than that, what did you think? What was your feeling differently? 2017 versus 2026.
[00:03:00] Speaker D: Yeah. Although the, the area where the convention is has slightly built up from where it was in 2020 17. But yeah, I mean, you know, I think probably the, the most concrete changes or just the size of the meeting itself. So I don't know what the exact number is.
[00:03:21] Speaker B: People?
[00:03:21] Speaker D: Yeah, I think there were 13,000 actually, if you include the virtual people. And There were also 8,000 or approximately 8,000 abstracts that were submitted including the meeting. So those are, you know, 8,000 different stories of scientific discovery across the world.
And actually another thing that I don't know if it was the case before, although I suspect it wasn't. There actually is a more non US presence.
[00:03:49] Speaker C: Yeah.
[00:03:50] Speaker D: Where the majority is actually not from the U.S. there's still obviously a very large U.S. contingent, but it just shows how the global reach of the conference has expanded.
[00:04:03] Speaker B: We should add that you were the co chair of the whole thing.
Yes.
[00:04:07] Speaker D: Yeah.
[00:04:08] Speaker B: So Dave had to review all 8,000 abstracts while Chris listens to these two old men speak. Let me just develop this. So my memory of 2017 was bland and I don't mean that meanly, but I mean there was a lot going on in the biomarker space, but it was all deep in the wings, meaning none of it was ready for clinical prime time in the diagnostics. And you saw that reflected in the industry space where there were very few booths vending things that were available for clinical practice and of course therapeutics. I think. I don't know if that was yet another meeting where a negative trial was announced or it was in between yet another negative trial. But you know, the same sentiment for therapeutics. But I think 2026 was quite different, don't you?
[00:04:54] Speaker D: Yeah, for sure. I mean, you know, I think 2017 we were probably very excited about Taupet at that point and so there were some advances in biomarkers. But the therapeutic landscape has obviously changed dramatically and just the richness of the science I think has really progressed in a significant way. And for sure the comment about the amount of work that's being done actually that's, that is translating to the patients that we see is, is dramatically different now than it was in 2017.
[00:05:29] Speaker B: So I want to hear one thing that stood out for you for that. But before you do, maybe Chris, what stood out for you? Like big top line thing that you take away from London.
[00:05:42] Speaker C: I mean, I think that the real Big difference. Looking back from 2017 where I was not there because I was starting my internal medicine rotation of third year of med school after finishing my PhD. You were close on high school, but I think the right. The big difference is, like Dave said, we were excited about Taupet in the research setting. And I think that my biggest takeaway from this meeting was how much of it was about applying biomarkers and drugs to clinical practice and getting data instead of being from highly curated research cohorts, being from people that we're seeing in clinic.
[00:06:18] Speaker B: What about you, Dave? What was your sort of top line field takeaway? Gestalt.
[00:06:22] Speaker D: Well, I definitely agree with Chris that a lot of the meeting was focused on the implementation of therapies and what people's experience was with them. That is really a shift in the field from more descriptive studies of what we see in patients and understanding biomarkers and predictors and more moving towards how do these therapeutics influence outcomes both, you know, positive and negative? I think a big take home in that space now, a couple of years into anti amyloid therapy, is that these drugs are able to be implemented in a safe manner across a number of different settings at levels, you know, in terms of risk, at least with regard to side effects that are similar to, if not slightly better than what we see in the clinical trials, which in many ways is incredibly comforting because there was a great fear that in the clinical trials that would be the best possible scenario with regard to side effects. And in fact, actually in the real world, it's anything a little bit better.
[00:07:37] Speaker B: Leave it once again to the field of Alzheimer's to upend what we think is the norm, which is, you're right. In clinical trials, we think that's the drug at its safest. And then in clinical practice, it's like, let the teenagers have at that. It was. It's almost been a little bit of the opposite. And I think in some sense, probably the drugs are saved by their complexity. If they had the same risks, but they were easy to dose and whatnot, and we might see things a little wild, but because they're in some sense so complex, maybe their complexity has been their savior. My big takeaway from 2026, 2017, was how damn hot it was. I mean, Europe's on fire.
We actually had a tropical night in London, meaning it never cooled off until. And the underground was truly closer to Hades than I have liked as well. Painful advantage, by the way, to go see Hades as well at the theater. And I bring that up not just to be witty about the temperature. But the first, you know, I think another theme I took away from the meeting was the greater attention to the exposome, to, you know, the world around the brain and how it impacts the brain's health and also efforts to change that world. More focusing on individual habits, if you will, than the environment. But the first session I attended on Sunday was a speaker from Japan who presented data on how extreme heat has two effects on actual outcomes. Early on, raises death rates, no surprise, but then a few years later after adjustments. So like all studies subject to the, you know, how much have you adjusted for? But it's a pretty compelling database, raises the risk of developing dependia. And a companion presentation from a group about the extreme effects of pollution on brain health data that sort of emphasized how our brain health is affected by the world around us. And we were living it quite literally in London, where there were temperatures that were quite outrageous. Let's dive in a little bit more diagnosis before treatment. So let's maybe dive into the diagnostics and the biomarkers. Are we still putting PTAC217 as the emperor of all biomarkers or not?
[00:09:39] Speaker C: I think right at that time in the field that I think this was really shown at the meeting that I think that right now Ptatra 17 remains our best marker for kind of identifying amyloid and tau, but that there's a big interest in moving and understanding a lot of the other changes that are going on alongside that to the immune system, to synaptic health. And so that's where proteomics, I think, has really started to be amplified and really had a big role at the meeting this year, where not only can we look at PTOT217, but we can look at how shifts and PTOT17 are accompanied by rises in some of these kind of immune markers beyond just what we've used in the past, things like tfap, as well as in kind of markers of synaptic integrity. So we have to learn a new neuropontrexin. Mptx is going to be one that's. Yeah, that's going to be coming more and more, I think, into the lexicon because of its ability to kind of measure some of the more subtle changes that may be occurring early on where the neurons.
[00:10:50] Speaker B: What is that measuring?
[00:10:52] Speaker C: It seems to be a pretty good marker of kind of synaptic integrity.
And so it may be a little bit more sensitive before neurons themselves are actually dying. But the kind of those synapses, the connections between them are being impacted. It seems like these different proteins in the neurocontraction family and PTX maybe are going to be some nice markers that maybe are more predictive of things like cognitive decline over time and might be impacted by multiple pathologies, not just Alzheimer's.
[00:11:26] Speaker B: These are blood based blockers.
[00:11:28] Speaker C: Yes. So they're both. They can be in the CSF or in the blood.
[00:11:32] Speaker B: Yeah. Dave, before I have you weigh in on Q17 and I know you actually did some rather thoughtful writing on it that came out at the same time, so. But what I hear you're saying, Chris, is the promise of a measure, not just of a disease specific measure of your brain health, but a cross disease measure of how well is my brain doing? Are my neurons beginning to become dysfunctional before you start seeing things like atrophy? A link downstream effect of neurons dying.
[00:11:59] Speaker C: Exactly. And it's been something we've been looking for in the ad space is something that's maybe a little bit more towards that neurodegeneration side of things.
You know, in the ALS world that's this other protein, NFL. But when we've tried that in Alzheimer's disease, it hasn't always been the most helpful. And so this is getting us past amyloid and tau and onto that nerve generation stage. And so, you know, I think more to learn on that level, but that's kind of, I think, the next kind of exciting thing that might be coming.
[00:12:33] Speaker B: So. So once more for our listeners. The name of this protein proteomic biomarker
[00:12:37] Speaker C: is so it's the easy way is nptx. There are a few different ones related to it, but neuropentraxin is the long mouthful to fill that with.
[00:12:47] Speaker B: All right, we'll keep our eye on it. Dave, P. Tau217, what are your thoughts?
[00:12:51] Speaker D: Yeah, so I mean, I think it still is probably the at least of the sort of biofluid based biomarkers or certainly blood based biomarkers.
The measure that I think is the most clinically practical that we can get and does, as Chris mentioned earlier, tell us about the likelihood of amyloid in the brain as well as I think. And there's more and more data supporting the idea tells us a little bit about the staging of the disease as well, for which other biomarkers in concert with it might be particularly helpful. But one of the other areas that was a major theme of the meeting was this idea that we are heading towards the possibility of drugs that could succeed in preclinical trials of Alzheimer's or trials when people are asymptomatic, two of which will read out in the next year to two years and trying to think about how markers that are clinically practical like PTAB 217 might help us in figuring out who patients who are the prospective people that, or individuals that would benefit the most from these drugs. And so there were, there was one very prominent session from a number of groups, including the group at MGH and at Mayo as well as, you know, UCL University College of London that presented data demonstrating the predictive value in cognitively unimpaired people for their absolute risk of developing cognitive impairment in the future. Which obviously is going to be a really important thing for us to know if we're treating people at a preclinical stage. Because you really only want to take a treatment if you're likely to develop symptoms during life. And I guess what I might say from the sort of take home from that data is that a measure like PTAU217 does provide a fairly strong amount of risk stratification for the likelihood of developing symptoms at five and 10 years, but are far from deterministic.
[00:15:06] Speaker B: What's your vision maybe based on what you see and what's needed so that we can give people a good, a reasonably solid five year window of your risk. What do you, what do you see as our future here?
[00:15:18] Speaker D: Yeah, I think, I think, you know, the blood test for sure is going to be I think an important component. I think one of the challenges with most of the studies in these populations is they come from these very sort of cleaned observational types of studies that are not necessarily highly representative of the population, both with regard to things like education, ethno racial differences and certainly, you know, comorbid medical kinds of conditions. And so I think things like for example, vascular risk likely will influence your, your risk of developing symptoms in the future.
You know, if you're likely not to develop symptoms in 10 or 15 years, but you're more likely to pass away from something else that will certainly influence the likelihood of your wanting to think about treatment. And I think all of that goes, you know, implicit in these kinds of discussions is that's in the context of treatments that are potentially expensive and have risk associated with them, particularly upfront risk. If these drugs were, which is the
[00:16:26] Speaker B: case, which is two anti amyloid therapies to antibiotics for now.
[00:16:33] Speaker D: Exactly. And you know, your risk with those drugs, at least as far as we can tell, is to some extent actually in the first three to six months with those drugs. And so if you're likely not going to develop symptoms to 10 years from now and your likelihood of again, some other medical issue coming up in that time is of a certain degree that may push you to not want to accept as much upfront risk.
[00:17:00] Speaker B: Our field is sort of rapidly walking into starting to talk like cardiologists, for example. Chris, let me pivot to you here. I went to, you know, in light of what you saw in London about our ability to measure what's going on in the brain, particularly in the sort of cognitively unimpaired space, what are your thoughts about our future, our actuarial future, for predicting our brain health? What stood out for you?
[00:17:22] Speaker C: Yeah, I mean, I think along with kind of this idea that we're going to need to use blood based biomarkers because they're clinically the most accessible, I do think that a lot of what I saw this year was kind of a little bit of a push back in the field. A little bit where over the past few years it's been how ultra sensitive can we get to detect the lowest amounts of pathology to now that we're using this in clinical practice and making decisions and treatment decisions based on it, we really do need to maybe take a step back from ultra sensitivity to ultra reliability.
And so I do think there was a little bit of a push back this year around kind of while we have a marker that may be really, you know, sensitive if it has quite a bit of noise in it. Yeah, the ability to detect biology beyond that noise goes down. And so I think that that was a big push. And so I do think that while screening with these blood based biomarkers is going to be important as we think about building these sorts of risk calculators. I think part of what is going to be important from an actuarial standpoint is how do we use our kind of what are in reality, particularly in a lot of parts of the country, finite resources about who should be getting PET scans. What is the likelihood that that blood based biomarker test is giving us a true result and is a person who's at higher risk that would be warranted to kind of go to a higher level?
[00:18:57] Speaker B: I just can't see PET scans becoming part of the standard of practice in the cognitively unimpaired space?
[00:19:04] Speaker C: I just think the scaling I think it depends on. Yeah, I mean, I think it depends on the drug that you're going to offer. I think if it's a drug that has a reasonable amount of risk associated with it, that you're going to want to be certain that the person you're treating has the problem you're trying to treat. I think also from a cost perspective, depending on the cost of these drugs, you probably want to make sure they have the disease.
[00:19:27] Speaker D: Some of this does come to like, you know, economic modeling. Right. Because if you truly did prevent the disease from occurring, a $3,000 PET scan might actually not be that much expense relative to the outcomes. I think another thing that our field, and this was a theme not just in the prediction of future cognitive decline, but also in symptomatic patients that we're struggling with, also is trying to best understand what the drivers are of someone's symptoms within these data. When we look, and this was a comment we made in the editorial for the one paper and Jamaica with these data, is that even people who have very low levels of these biomarkers, presumably, if we assume the test was correct, you know, a certain proportion of them still develop cognitive impairment in the future, which suggests there is some base rate of non ad driven processes that can cause symptoms.
[00:20:28] Speaker B: Let us not forget alpha synuclein and TDT43 and vascular disease. Yeah, yeah.
In combination.
[00:20:35] Speaker D: Yeah. And so I think we are trying to grapple with how can we decompose in any given patient, whether it's for prediction or someone who comes to you symptomatically, what are the things that are most causing their symptoms? Because that might influence, again, what drugs that we might apply. And I think there was a lot of work at this meeting with progress, but I don't think we're there yet, or trying to capture some of these other co pathologies, trying to capture quantitation of things like alpha synuclein and TDP43.
We're trying to subtype Alzheimer's symptomatic patients or patients with dementia or mild cognitive impairment that have some degree of Alzheimer's disease into categories that might help us better tease apart those different kinds of contributing effects that I think we're making progress, but I just don't think we're at that point where we can confidently distinguish those kinds of factors that influence symptoms in our patients.
[00:21:42] Speaker B: I want to pivot to treatments before I do. I think one of the takeaways, I do want to say summatively, I'd much rather be having these kind of conversations about the struggles over matters of economics and actuarial issues than where we were in 2017. So listeners do not take away any sense of discouragement, but rather, these are challenges. My only concern is, as a country, America is really good at innovation, but we're not very good at consolidation. And I think there's going to be a need if, say Trailblazer 3, which is tenantumab, or ahead, which is lecanemab or preventron, which is, and we'll talk about in a minute, trontaminumab are positive.
This is where as a country coming together to sort of agree how are we going to take the FDA approval, let's pretend that all that happens and move it into practice in the setting of Medicare, private insurers, how to organize all those various separate actors to come up with what's the right way to proceed. So a bit of a policy editorial there, I suppose.
Let's pivot to treatment. For all the progress in our biomarkers, there's been also progress in our therapeutics. Although there's only two drugs, it's encouraging. But just the two. Donanemab and Nikinumab. Eight takeaways from the data that were presented there, ample abstracts from both our colleagues at Esai and Lilly on these two drugs. Any takeaways that you all took from the presentations? Abstracts.
[00:23:04] Speaker D: One of the.
[00:23:05] Speaker B: Of the many 8,000,
[00:23:10] Speaker D: I would say one, I think two. There are only two drugs, but we had none for 20 years after memantine was approved. So I'm still quite pleased about that.
[00:23:25] Speaker B: I did not see the abstracts on Mementine.
[00:23:27] Speaker D: Yeah, I mean, I think this year was not a year where there were lots of new clinical trial results that came out, but there was. What did come out, I think was very exciting and just the, you know,
[00:23:46] Speaker C: one, one, I think, theme of the
[00:23:48] Speaker D: meeting and was included in one of our plenary sessions was these brain shuttle approaches which I think are going to revolutionize CNS central nervous system disorders in general. Because one of the tricky things about treating brain diseases is that there's this thing called the blood brain barrier which blocks a lot of particularly larger sized molecules like antibodies, but even to some extent, things like oligonucleotides, which are these RNA sequences that can block certain proteins from, from being produced in, in the brain.
And these shuttles are essentially tacking on molecules that allow receptors or other proteins to kind of pull that drug across the blood brain barrier to better target what we're trying to get within the brain. And so I think, you know, that the, within our field, the example of this that's been quite impressive is taking what was an antibody that had somewhat limited amyloid clearance, this drug called cantonerumab, and adding in one of these shuttles in which it now shows extremely potent clearance of amyloid from the brain. And in Fact is actually at least based on the data that's come out so far, can be delivered more safely, it seems than our current drugs. Yes, the technology is amazing.
[00:25:20] Speaker B: Yeah, the presentation of the plenary that kicked it all off from the gentleman from Denali Therapeutics was really inspiring that the Maginot line, otherwise known as the blood brain barrier has been penetrated. Chris, did you have any takeaways on any of the presentations on any of the existing therapies that are out there? Didenum learn lecanemab. And by the way, it was interesting that FDA gave ECI a little Christmas gift in August with a approval for sub qdinamab to start as opposed to starting on iv. So the anti amyloid wars now enter a new phase where we have an all IV versus an all sub Q therapeutic. The latter requiring therapy seemingly indefinitely, the former of course for short term. So it'll be interesting to see any, any thoughts on that development in the field.
[00:26:03] Speaker C: Yeah, I mean I think I was going to say that you know you said we have two and I was going to say well but now we kind of have a third at least in the new version of one of themab 2.0 subcutaneous.
[00:26:16] Speaker B: What are your thoughts? Sub Q lecanemab versus IV donanemab. Dr.
[00:26:21] Speaker C: I mean I think you know that's going to be an interesting, I'll, I'll be interested to see people thoughts. You know it's something that in the Ms. World they've actually dealt with for a while which is that there was, you know, a monthly subcutaneous injection versus an every six month infusion. So you know, a little bit up the same medicine essentially. And they actually didn't see almost nobody was interested in giving themselves an injection once a month compared to an infusion every six months. So it'll be interesting to see does weekly versus monthly change that I'm not sure. You know I think from the data that we've seen is that we're still kind of in the scenario where we have two drugs that have pretty similar side effect profiles and pretty similar efficacy from a clinical standpoint from the trials. And so it is, you know, it's nice in one way and that it kind of comes down to individual choice for the patient rather than necessarily having to push one way or another based on some data.
[00:27:23] Speaker B: Yeah, choice based on convenience cost.
Dave, you're weighing on this one.
[00:27:30] Speaker D: No, I mean I guess it's another piece is just your belief, right.
[00:27:34] Speaker B: Belief core of medicine.
[00:27:36] Speaker D: One of one of the things that I think you know, we don't know is exactly the scenario you, you said earlier, Jason, which is that it's, you know, either one drug that you get for a, a shorter period of time versus another drug that you give for life but could take at home without having to come in for monthly infusions. And I think the jury's still out about whether there's any advantage to one versus the other, whether it could be the case that continuing or having like boosters of something like Donanemab in the future might be a benefit but still be less consistently given than lecanemab, which you still have to do on a monthly basis. There was some data with that brain shuttle drug that we talked about that even in people who were cleared, there seemed to be even further lowering of markers when the drug was continued beyond the initial placebo control period.
You continued to see, for example, gfap, which is a marker of inflammation in the brain, go down further in individuals who were treated after clearance, which might argue that you're still somehow reducing this negative inflammatory or, you know, immune based effect that's occurring in the brain beyond what you would see with just the sort of baseline level of clearance that we get on amyloid. Pet. No knowledge at this point about whether or not that has a clinical benefit, but it does suggest that the biology certainly still somewhat complicated even after we see, you know, amyloid clearance.
[00:29:20] Speaker B: Yeah, we're still working out the vocabulary, the nomenclature, what, what describes a healthy brain. Obviously in the end it's, you know, my cognition has not changed and I'm, my mind remains the way it was.
That's the bottom line. But in between that, these various measures of biology, I think as you gestured to earlier, Chris, you know, nptx, could that be one or microstructural MRI or any number of other measures.
It's going to be very interesting to see in the coming years what we talk about when we talk about a healthy brain outside of cognitive testing, which itself is up for grabs too, with new methods.
There was one other couple other studies that were promising we mentioned in research space, Trontinumab, the shuttle mechanism. Biogen gave us some results from the TELIA study. Or Celia, I'm not sure is what the C is pronounced as there. I don't know why it was called Celi, but anyway, which was the Derenerson study, the antisense oligonucleotide. Were either of you able to make that presentation?
[00:30:17] Speaker C: Yeah, yeah, I was able to go. It was exciting that we had a new, you know, target that yeah. So the target here was like, it had response. So we're targeting tau now instead of animal.
[00:30:28] Speaker B: Yes. Tau finally had its, its moment on stage. Yeah. Although it wasn't such a clean result.
[00:30:37] Speaker C: Yeah, you know, I did.
[00:30:38] Speaker B: It wasn't dirty, but it was complex.
[00:30:41] Speaker C: Yeah, I would agree, you know, I think so that the results of the. I'm going with Celia because I can say that a little easier. I don't know which one it is, but that was really, you know, a dose finding study to look at, you know, what the appropriate dose was. And you would expect, you know, the preplanned ideas that if you give more of a drug, it has more. More of an effect. And what they saw was actually that the lowest dose that they gave had their robust effect
[00:31:11] Speaker B: to the high dose.
[00:31:11] Speaker C: You got to the high dose, it had less of an effect.
[00:31:14] Speaker B: What was the biomarker response? How did the biomarker response of tau behave too?
[00:31:20] Speaker C: So the biomarker response looked a little bit more like a dose response effect where the lowest dose had a benefit, the next dose up had a higher benefit, and then there really wasn't much actual added benefit from the highest dose of the drug that they gave.
[00:31:39] Speaker B: It's a little odd. It's a little odd that the biomarker didn't follow the clinical.
[00:31:44] Speaker C: Yeah, I mean, I think part of that is it's a different drug target. So this is. Now we're not targeting, removing a plaque that we know is there and is not doing things correctly. This is, you know, a drug that's looking at turning down a protein. And so there may be really beneficial effects to that, but there could also be harmful effects. And so that is where you might get this kind of U shaped curve where there's a Goldilocks dose, essentially.
[00:32:13] Speaker B: Brilliant. I like that. I like that. The three bears, which are, which. Which porridge is just right. Which does bring us to the Lilly study, which was a negative study that was not present. Well, there was abstracts of it. Did you have any thought where they showed a robust response of tau lowering reduction but on drug component to placebo, but a negative result for the drug. In fact, almost a harmful result. I was wondering if you had any put those together thoughts or maybe there's too much synthesis going on here.
[00:32:45] Speaker D: You know, in terms of the Celia study, it's also really the first gene therapy within our field that has shown any kind of signal. And that in of itself is kind of a remarkable stage for our field as we're really, you know, at very fundamental levels targeting the Biology. What I would say about, I mean, I think, you know, one of the challenges with our biomarkers is sometimes it is hard, you know, to know what to expect to see because, you know, I might have, I might have expected for a drug that lowers Taurus that its main effect, if it's beneficial, will be in preventing the spread of tau rather than actually lowering the tau that's already there.
It could be that the lowering of tau that's already there is more of just a surrogate of the fact that the drug is having some effect on tau but not necessarily reflective of its beneficial.
[00:33:40] Speaker B: So it's sort of, I think we would call that a meta surrogate.
[00:33:44] Speaker A: Yeah.
[00:33:45] Speaker D: So something of that nature.
[00:33:47] Speaker B: I want to mark this as the first time that that phrase was used in the history of medicine, and medicine can trademark it. Thank you.
[00:33:53] Speaker D: But, you know, I, I, so I don't, I guess I, it doesn't surprise me that we would be seeing potential discordances between outcomes. The only other thing I'll say, you know, with regard to the, the dose response for the Celia study in terms of the, the tau effect is it was, there was, it was pretty much a floor effect. So there was a somewhat more robust effect in the higher doses, but they were sort of marginally different from the lower doses of the drug.
And so again, I think it's hard to know what to interpret.
To me, it is not intuitive though, that lowering how in areas where there's already injury necessarily saves those neurons and it more is about preventing its spread.
[00:34:39] Speaker B: Chris, I know you were in grade school and these studies came out, so this is. So I would educate you over the old guy here, but once upon a time we had a theology about amyloid, that if you remove it, you should see less atrophy in a brain compared to people on placebo. And the early studies showed the opposite, that there was, quote, more atrophy. And that's of course caused a lot of people to say a host of things in retrospect. Over time we learned, and I think Nick Fox and others have shown eloquently what we're seeing was the effect of removing amyloid on volumetric changes, not changes in the brain tissue. But I think it all just more emphasizes that I think we have to not let our beliefs about our biomarkers become what we think are the facts. And just to simply listen to the data. Yeah.
Gentlemen, we're sort of at top. We've covered sort of overall views of London, including the extreme heat.
London now faces the challenge of how to install air conditioning, which I think will be a real challenge for much of Europe. And the energy demands of that, together with AI's energy demands. We talked about the diagnostics and the emerging excitement there and the therapeutics. Let me just give each of you sort of last minute thoughts before we wrap it up here. Dave, any last minute closing thoughts or whatnot? First of all, congratulations. Great job. Coach hearing, by the way. Really.
[00:35:56] Speaker C: Thank you.
[00:35:56] Speaker D: Yeah, no, it's again, I think it's a somewhat laborious job, but it's helped. The success of the meeting is very much helped by the quality of the science. And I just, you know, I been on the scientific program committee for a number of years and at various cycles and I just really have to say there's much, much more high quality science coming from around the world and actually more and more new attendees, people who have never been to AIC are coming each year and I think that's a reflection of, of the field and I just think we're at the beginning of a more mature stage.
[00:36:38] Speaker C: Similarly, I think it's really exciting to look back, you know, compared to where we were even, you know, five years ago with no approved therapies, everything still being in the research setting to now where we're doing blood based biomarkers which didn't exist and people who are receiving therapies which weren't available all in clinical spaces around the world.
So not just from these highly curated cohorts from the United States and Western European countries. And so I think that it's exciting to see that, to see these kind of new people getting involved in the research side of things because it impacts them in their clinical practice where they are. And so I think that'll be exciting and be exciting to see what comes up next year in Chicago where Dave tells me the White Sox play along with the Cubs.
[00:37:36] Speaker B: Yes, we will be back to Chicago next summer. That's where I went to college and medical school and did my fellowships there too. So it'll be a return one. My takeaway actually in the end was I was give a shout out to the Libby study, which was the study that tested a combination of THC and CBD in individuals with agitation with dementia who had agitation, were at advanced stages of disease and showed that it was one of the most elegant sort of just clear drug greater than placebo effects across all endpoints. It was a really quite encouraging study in a space of therapeutics for a patient population, namely individuals with severe stage disease which had really been difficult to treat. Of course, the next challenge will be getting that formulation available in the marketplace because it was a formulation was made specifically for the trial and the investigators emphasize it's not something just going out and buying a couple hits of medical marijuana. So. Oh, well, hope that'll work out. Gentlemen. Thank you so much, listeners. Stay tuned in a year for us to return again and recount our takeaways from AAIC in Chicago. Thank you, Dave. Thank you, Chris.
[00:38:42] Speaker D: Thank you.
[00:38:43] Speaker C: You too.
[00:38:47] Speaker A: Thanks for listening to this episode of the Age of Aging. A special thanks to today's guests, Dr. David Wolk and Dr. Chris Brown, and to Dr. Jason Karlewish for leading that conversation.
If this episode resonated with you, please subscribe, leave us a review or share it with somebody who would appreciate it. It makes a real difference in helping others find the show.
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[email protected] the Age of Aging is a pen Memory center production made possible by the generous support of the the Michael Nadoff Communications Hub Fund. Our team includes Morgan Adams, Dahlia Elsaid, Jake Johnson, Jason Karlewish, Emily Largent and Allison Lynn. And a shout out to our summer intern, Misha Norton, who's now back at school. We wish her the very best in the new school year. I'm your host today, Terrence Casey.
