Podcast – ADPD 2024 Conference Highlights – Part 2

Voice Over:

The Dementia Researcher podcast, talking careers, research, conference highlights, and so much more.

Dr Emily Maguire:

So we are back with part two, recording on location from Lisbon in Portugal to share highlights from the last three days of this year's ADPD conference, one of the biggest conferences in the calendar with over 4,000 delegates sharing groundbreaking science. I'm Dr. Emily McGuire, and I'm a postdoc working at Cardiff University within the lab of professor Julie Williams as part of the Dementia Research Institute. So my work is generating IPSC models of late onset Alzheimer's disease based on the genetic risk for Alzheimer's disease. Joining me to share their ADPD conference highlights are Dr. Heather Snyder, Dr. Timothy Siegert. And last but not least, Dr. Daniel Erskine. Okay. So hi everyone.

Dr Tim Siegert:

Hi. Thanks for having us.

Dr Heather Synder:

Hi.

Dr Emily Maguire:

Hello. Okay, so we're going to start with a round of introductions and also I'm going to give you a chance to talk about any work that you have while we'll be presenting this week. So first Heather, do you want to go first?

Dr Heather Synder:

Yeah, absolutely. Happy. Thanks so much for having me and looking forward to the conversation with all of you today. I'm Heather Snyder. I'm one of the scientists on staff at the Alzheimer's Association and in my role at the Alzheimer's Association, I oversee all of our funding portfolios. So today the association has active and currently committed over $405 million at work in over 56 countries, more than 1100 projects. So while I haven't presented at ADPD, it's been really exciting to see so many of our funded researchers presenting their work, the latest findings, and some of them have been presented by the researchers themselves and some of them have been presented by their mentor and their PI. So I look forward when we talk a little bit in more detail about some of the highlights and the things that we've seen to talk about some of that work.

Dr Emily Maguire:

Awesome. It must feel really good to see some of the work that you've funded come to life.

Dr Heather Synder:

It is, and we're a science-based patient advocacy organisation. And so at the end of the day, how the science translates ultimately to our understanding of the diseases that cause dementia and ultimately translates to helping those that are affected. That's really what the work's all about. I think that's why we're all here. That's why so many people are here at this conference as well and telling that story and then telling that story as we go forward ultimately to improve diagnosis, early diagnosis, early detection, greater understanding of the disease, new paths of therapy, better care overall across the entire continuum for all of these diseases. That's the key.

Dr Emily Maguire:

Yeah. Certainly. I don't know what us academics would do without people like you. So thank you.

Dr Heather Synder:

That's an ecosystem we're all in.

Dr Emily Maguire:

Yeah. Okay. So Timothy

Dr Tim Siegert:

Great. Yeah, and it's not just academics that get support. So we have Alzheimer's Association support to my co-founder Steve Stripmatter at Yale part of our programme where we have clinical results that we're presenting in just a few minutes. So save some of the best for last I suppose, yeah. So my name's Timothy Sigrid. I'm a co-founder and chief operating officer of Alex Therapeutics. We're a small biotech company based in New Haven, Connecticut spun out of Yale University with my co-founder Steve Stripmatter, who's the chair of neuroscience at Yale. And we're really focused on understanding and drugging the process by which A-beta oligomers interact with synapses and drive synaptic dysfunction and loss as a disease modifying therapy for Alzheimer's. And there's a lot of support. That same type of pathway could be activated in Parkinson's disease with alpha-synuclein aggregates being the neurotoxic species. And we have funding support from the Fox Foundation. So we've been advantageously benefiting from a lot of these different grant funding agencies, equity funding to help drive some science forward into the clinic and give some hope to patients.

Dr Emily Maguire:

Well, thank you. It is always nice to hear from someone who works in industry, I having always worked in universities. And good luck later. We'll all be rooting for you. Thank you. Okay, so Dan, I know you've been on the podcast before, but please introduce yourself.

Dr Daniel Erskine:

Yeah, hi. So I am Daniel Erskine. I'm an Alzheimer's Research UK senior fellow, and I'm also a senior lecturer in neurodegenerative pathology at Newcastle University in the UK. Primary interest in Lewy body diseases, particularly Lewy body dementia. I gave talk this morning? Yeah, unfortunately time really does escape at conferences, especially ones that I would say are, forgive me, but American style conferences like this one that start really early and finish really late, so time really does fly. Yeah. So I gave a talk earlier about some of our post-mortem findings from both Lewy body dementia, post-mortem brains, but also the brains of children with lysosomal storage disorders that have pathological overlaps with these inverted commas, age-associated diseases. So yeah, I'm really looking forward to chewing down on everything we've been looking at over the last few days.

Dr Emily Maguire:

Nice. I hope your talk went well and you got some interesting feedback. Did you?

Dr Daniel Erskine:

Yeah, interesting, interesting discussions. Yeah, very much so.

Dr Emily Maguire:

Nice. Perfect, perfect conference experience then.

Dr Daniel Erskine:

Yeah, I think this is the value. It's something that you really can't recapitulate online. I mean the science to some extent, I don't think always happens in the lecture halls. It happens in the coffee shops around the posters.

Dr Emily Maguire:

Definitely.

Dr Daniel Erskine:

It's the chats and discussion, it's the collaborative nature of science. Very much so.

Dr Emily Maguire:

Yeah, it helps us put our own work into perspective and also think about it in different ways.

Dr Daniel Erskine:

Absolutely. I mean, if you even look around this table, this sums up the collaboration that these conferences bring together. It's not just academics. I talk to academics all the time. I don't talk to people who work on polymer based therapies, which is very relevant to my work or patient science-based patient advocacy groups. It's the power of conferences that brings us all together.

Dr Heather Synder:

I think I've done more on the stairs and had more conversations on the stairs going up and down, and in that long hallway than... I completely agree with you.

Dr Tim Siegert:

And it's made the forums really informative too, where you have different people from across academia and industry or philanthropy talking about clinical development and Alzheimer's disease, that a lot of these people are siloed but still have some similar and shared problems that they're trying to address.

Dr Emily Maguire:

And I also feel like it takes a variety of different kind of people from different kind of jobs and industries in order to actually bring things to the clinic overall rather than just one type of scientist. So, okay, we're done with the introductions. So next, let's get onto the conference highlights.

So just like with part one of the show, we have a pretty simple format. So essentially we're going to go round three or four times and I'm going to ask you to talk about your best bits from the conference and the talks or posters that you've enjoyed the most and why. And basically it'd be great if you could just give a summary of them and also talk about the main takeaways. So in the first part of this two-part special, we covered Tuesday to Thursday morning. So now we're going to talk about the talks and posters from Thursday lunchtime onwards. So Heather, can you please share your first highlight?

Dr Heather Synder:

Yeah, no, I mean there's been so much to discuss. I think we were chatting a little bit before we went live here and just, there's been a lot of different topics and a lot of different threads of research and how it's come together. But one of the talks that I know many people from our team at the association really enjoyed was Dr. Bill Jagist from Berkeley who talked about cognitive successful ageing. So how do we think about successful cognitive ageing? We talk a lot about these diseases that cause dementia and what is going wrong or what is changing in the brain during these diseases, but we don't talk as much about what is happening in those individuals that are successfully ageing without cognitive decline. And so Bill talked a lot about some work from one of his post-docs by Dr. Stefania Garzoli who happens to be an Alzheimer's Association of research fellow.

So it was really great to see her work on that main stage as well as we understand more about that underlying biology, as we understand more about the specific brain regions that might be at play and where there might be perhaps a greater connectivity or regional differences in the brains between people that are successfully cognitively ageing, versus those that may not have that same resilience. That can give us a lot of insights as we think about what are those interventions, what could be some of those strategies to target that biology maybe even earlier, so that we can strengthen that in individuals to help really in that successful ageing and maintain the integrity of cognition.

Dr Emily Maguire:

Yeah, totally. I feel like it was indeed one of the main themes at this conference, the resilience aspects, what's happening in people who are kind of ageing in a normal or cognitively healthy way. Yeah, it's very...

Dr Heather Synder:

And what does that look like, particularly in the underlying biology. So I think, well, I'll talk about that next. I'm not going to give away my next highlight.

Dr Emily Maguire:

One highlight at a time. Okay. Tim, would you like to share one of your highlights?

Dr Tim Siegert:

Yeah, sure. So at Alex, we're wrapping up our phase one B study now and I'm presenting that. So I spent a lot of time thinking about phase two and I think one of the exciting things over the past, probably year two years, once we've had monoclonal antibodies start showing they're successful has been the biomarker tools that are available to measure response to drug treatments. And so I thought a really phenomenal tour de force discussion on P-tau biomarkers from Kaj Blennow yesterday was really fantastic because one of my favorite questions to ask people is, "Okay, we know we can remove amyloid from the brain. We know P-tau217 and P-tau181 go down, but what does that actually measure?" And there's a lot of hand waving that says you're measuring and that's related and a biomarker of amyloid removal, but tau is an amyloid, right?

And there's an interface between those. So, Dr. Blennow did a phenomenal job of a tour de force historical assessment of P-tau and how they move not just in Alzheimer's disease, but it includes all Creutzfeldt-Jakobs disease, which is implicated in prion protein signaling and misfolding across these neurodegenerative diseases. You see P-tau come up and you see different species of P-tau come up. And so the question is, if you see the same P-tau move and a disease that doesn't really have any amyloid pathology, what does that mean? And how can you use those tools in a clinical trial to see if your drug that's targeting synapses might be having a disease modifying effect? So I thought it was really phenomenal trying to dig down deeper into these questions for beyond just these pathologies defining disease and disease stage, what actually are they measuring in terms of response to therapies?

Dr Emily Maguire:

Well, that sounds really awesome. I didn't see that one, but I'm really glad that they have them recorded and we can watch them later because it seems like it was definitely one to watch.

Dr Tim Siegert:

Yeah, I mean, you could give a 25 minute talk on it if you read all the literature and probably take you four years to get through all of those biomarker studies.

Dr Heather Synder:

I'm surprised you got it in 45 minutes even.

Dr Tim Siegert:

Well, it was a lot of, "Look at this paper, look at this paper, look at this paper," and some highlights.

Dr Emily Maguire:

Well, thank you. And Dan, do you have...

Dr Daniel Erskine:

Actually fits in very nicely with what you were just saying? I do think the theme of resilience has been such an interesting point. I caught a really excellent talk. Again, my perception of time slightly altered, I'm pretty sure it was yesterday. There's a guy called Tain Luque, really interesting post-mortem study that kind of adopted an almost a contrary approach to what most post-mortem studies did or what they do. He essentially looked at the slopes of cognitive decline in patients that were assessed sequentially over time and looked at the numbers of neurons and different types of neurons and also neurodegenerative pathologies and basically looked for which of those associated with preserved cognition. In other words, a less steep slope of decline. Super interesting. So for example, in Alzheimer's disease, they'd observed that layer two, three pyramidal neurons were associated with reserve with less severe decline, all other things controlled.

And they also noted then with Lewy body disease, which I found very surprising, they found a microglial cluster was decreased in those. Now that's interesting to me. I look at a lot of brains and inflammation is not something, it's something people who do models talk about a lot in LBD. People who look at brain tissue don't really so much because you don't see obvious evidence of gliosis in the same way that you would in Alzheimer's disease or multiple sclerosis. So it was very interesting to see that microglia that we don't normally associate with LBD in the same way we would Alzheimer's disease seemed to be decreased, seemed to be of lower abundance in those that appear to have a preserved cognition for a longer period of time. And I just love this approach because it really is, instead of looking for disease associations looking for health associations, which I really liked.

Dr Heather Synder:

So I just have to say that is incredibly cool. It'd be really interesting if they went the next step and then looked at some of the underlying genetics to say, is there a linkage or is there anything that is perhaps informing the immune response or how the immune response in those individuals is, just a fascinating across all of the trajectory that they're doing.

Dr Daniel Erskine:

I mean, I totally agree and I think the immune system, I always say that there's two different types of people that work in the field. There's neuroscientists and there's immunologists because immunology is just such a complex and difficult field. But from what I understand, so I'm prefacing what I'm saying with that, but in case I say something that's silly, but as far as I understand that things like the history of immune challenge, for example, can play such an important role in mediating the future immune response. So I mean obviously as we come out of a global pandemic where lots of people have a very stimulated immune system, it'll be interesting to see what risk factors emerge from this. And again, that was something that was covered in some other talks was the COVID-19 link.

Dr Heather Synder:

I think there was one right before we came in here.

Dr Daniel Erskine:

There was, yes. So yeah, very interesting.

Dr Emily Maguire:

Okay. So should we do some more highlights and...

Dr Heather Synder:

Yeah, I mean maybe even just building off of some of this theme, and you talked a little bit about some of the P-tau work and where that is. There was a great presentation this morning from Nicholas Ashton who is currently in Europe, but is in the process as he ended his talk and moving to Banner, and he's recruiting, I think, for people in his lab. But he did a great talk in terms of thinking about some of the other contributing factors. So as we make these measures, how do comorbid conditions perhaps influence the measure and the assay and what does that look like? And so he was looking at some of the things around kidney function and some of that measure and really showed that we talk about this as being, "Oh, this..." And I've heard this in talks about being this incredibly complex or additive in terms of the complexity of how we interpret, but he showed this what I thought was this amazing graph which showed across all, I mean it had to be 50, 60, 70 different measures that the influence that kidney function has.

And tau was, kind of, right in the middle. It wasn't really one way or the other. It was somewhat in the middle in terms of its influence. And that just really was striking to me and that yes, we have to take these considerations into account, but the influence or the understanding we have of these biomarkers really comes into play with the clinical symptoms and the bigger picture of the disease depending on where someone is. But as we move earlier and earlier in that as well, taking this into account and really understanding it and the importance that real world data will have on that understanding is paramount. We're not necessarily going to get this from cohort data we need to have, it is going to be all kinds. And we were talking a little bit about that in terms of the multidisciplinary approaches, but needing cohort data, needing community samples and then tying that in with real world data that allows us to actually understand how these tools are really acting when we're out in the community and part of clinical care.

Dr Tim Siegert:

Yeah. Well I think maybe to even touch on that, there is a talk that Roche gave on one of the gantenerumab studies that they ended early because the primary one failed. And they went through evaluating what their screening structure was like. And now that we have these biomarker tools and plasma biomarker tools for screening with amyloid beta or P-tau and you want to use that as part of your patient selection criteria, what's your screen fail rate? And what they didn't mention was anything about whether they had any kidney function data on those people. And I would say if you're running a clinical trial, particularly with a small molecule, you want to avoid people who have major kidney failure or dysfunction. So maybe not quite as big of a deal early stage, but in a real world, world setting for patient diagnosis to make it easier to find patients, screen them and even make sure that the drugs are working, things like that are really important.

Dr Emily Maguire:

It is good that we now have more machine learning tools and things like that so that we can incorporate more and more of this data in as well when we're doing things like assessing patients and that because it's clear that it's more than just so much more than just about the brain when we're talking about these neurodegenerative diseases. Right?

Dr Heather Synder:

Yeah, I mean the brain controls everything. So actually it doesn't just stop here. And we hear so much about the vascular contributions and all of those pieces as well and how they all are intersecting with one another and the immune system, as we were just talking a little bit about.

Dr Daniel Erskine:

And I think a lot of these pathological proteins as well, there is evidence that they are accumulated in other parts of the body as well, especially the case for alpha-synuclein. I know that there's almost a bit of a race on defined sample, different parts of the body to see if they can be used as less invasive biomarkers than lumbar puncture, which clinicians in the United States are very happy to use UK clinicians.

Dr Tim Siegert:

I'm not sure I'd say that.

Dr Daniel Erskine:

That's a perception that we're always led to believe that that is something that's done a lot more in the United States than the UK.

Dr Heather Synder:

It's done a lot More in Europe. So particularly in Sweden and the Nordic countries, there's a really strong and in fact over-imaging in the United States, it's somewhat mixed and part of it is because PET imaging, but PET imaging is not widely available. And we've actually funded some work out of Washington University, St. Louis, to look at really across the Alzheimer's disease research network centres in the United States about what some of those perceptions is. And there's a discomfort. It's not necessarily something that clinicians are doing regularly necessarily. There is a perception of side effects and others, but where people are comfortable, they're definitely comfortable. And so it's somewhat mixed in that. But I think in research studies we do see that people are more, are often somewhat comfortable doing that and it is a decision between that or PET and other things. But yeah, it's definitely in the Nordic or the northern part of Europe, it is much more widely accepted. And I think EMA was really the first to come out with some guidance in that as well, much before the US. But there are now FDA-approved tests in the US and other things. So there is an accessibility. It is in some places more accessible than PET might be because there's not a pet image or a pet scanner, for instance.

Dr Daniel Erskine:

Interesting. I did not know that.

Dr Tim Siegert:

Yeah, it's a challenge when thinking about clinical trial design in terms of site selection because I think it is very site-dependent. Who runs the site? Is it someone with a heavy neuroscience background or neurology background or psychiatry background?

Dr Heather Synder:

I think well, the comfort with doing the actual test. I mean, do you have the resources? Do you have the facility to do it and do it in a way that is safe and right for patients? So...

Dr Emily Maguire:

I guess this is another advantage of conferences is that it brings researchers together from around the world as well, so we can talk about how things might be different in different parts of the world.

Dr Daniel Erskine:

Absolutely, yeah, and it's interesting of course, learning from what works and what does not work elsewhere. Yeah, definitely.

Dr Emily Maguire:

I feel like it's Tim's turn.

Dr Tim Siegert:

Yeah, sure. So another one I thought was really interesting on Thursday afternoon. So we think a lot about how amyloid beta oligomers bind to cellular prion protein, but there was a really great talk and we think a lot about the overlap between different neurodegenerative diseases, so Parkinson's disease, but even potentially like Creutzfeldt-Jakob disease or infectious prior diseases. And John Collins gave a really good talk following up his recent paper on iatrogenic Alzheimer's disease. So acquired Alzheimer's disease pathology from human growth hormone samples that were in the bank where patients were back in I think the '70s were receiving human growth hormone derived from human pituitary glands. And not only is there instances of infectious CJD from those samples is there now seems to be some evidence of infectious Alzheimer's disease from those samples. So really interesting to think. I think sometimes we're very siloed in how we think about Alzheimer's and then Parkinson's Creutzfeldt-Jakob disease or frontal temporal dementia.

And what I'm really interested in is are there overlapping mechanisms within those, not to say that Alzheimer's is infectious or acquired through routine medical care, that's not the case. But just to think about how these pathologies may all start from different types of sources. You can get familial disease, you wouldn't really get acquired Alzheimer's disease, but it's potentially possible. You can inject amyloid beta into the brain of a mice and they have neuro-degeneration, same with alpha-synuclein. So it's just like an interesting thing about are there overlapping therapeutic targets that you can go after where they might share pathologies or share mechanisms of not just spreading but also of neuro-degeneration.

Dr Heather Synder:

We had actually worked very closely with the Alzheimer's Association, Michael J. Fox Foundation, Western Brain Institute and Alzheimer's Research UK several years ago on doing a programme called biomarkers across Neurodegenerative diseases. With that in mind of that, there are some commonalities in where things might diverge or difference or you might have the same thing that you're testing or you're looking at from a biomarker perspective, but it may go to the right in one neurodegenerative disease and to the left and the other. Well, that's my right, that's my left. But either way they might diverge, let's go that way in the different diseases. And I think that gets to some like can you measure microglia? Is there a particular marker? This goes back to what we were talking about before, that perhaps in one disease that will be elevated in another disease, it would be lowered from a cognitively unimpaired individual.

And so does that give you some indication is that direction that people may go as they progress from those initial changes or from those and that commonality there is some, but then you also see some differences in terms of the networks of where and how the brain networks and the communication networks are overlapping among those diseases as well. So it raises so much of those questions, but there's also a lot of learnings that you can take from one to another in terms of some of the measures of CSF beta amyloid and CSF and what some of the considerations are for the pre-analytical processes to alpha-synuclein with some of the pre-analytical processes. And there's a lot of synergy between some of those that are overlapping as well. So it's again, I think one of the strengths of this meeting that brings those two spaces together and in a really unique way, we've seen that in presentations you'll have a talk on a very focused Alzheimer's disease related talk, your next talk is very specific to Parkinson's disease and some of the neuropathology related. And then your next talk might be on Lewy body dementia or on Frontal Temporal Dementia and on something more general in neuro-degeneration. And that type of intersection allows us to have some of those conversations.

Dr Tim Siegert:

Heather, I think you're arguing for a title change of the conference, ADPD and beyond maybe to go after there is discussion of pale discussion on ALS and Frontal Temporal Dementia and bringing these people together is great.

Dr Daniel Erskine:

I think it's such a good point as well about the sort of commonalities, and I think that is something this conference does really well, but I do think there's a growing consensus in the field that there are so many commonalities and mixed pathologies is the norm rather than the exception. The idea that we, as you mentioned, overlaps between these conditions between alpha-synuclein, Lewy body, Dementia, almost all of these cases have some degree of tie-in and Alzheimer and amyloid beta pathology. Nearly 50% of Alzheimer's cases have Lewy body pathology, probably most of them have some degree of inflammation. Vascular changes or almost vascular is almost invariable in these cases. And even genetic risk factors hugely overlap. So APO is a risk factor for Alzheimer's and Lewy body dementia-

Dr Heather Synder:

And cardiovascular disease.

Dr Daniel Erskine:

And cardiovascular disease of course, and of course vascular Alzheimer's disease. Most vascular risk factors are risk factors for Alzheimer's disease as well. So, so many commonalities. But even to dial down to the biological level, they're almost invariably associated with the accumulation of highly expressed tissue proteins. That in itself suggests commonalities because why is the unfolded protein response not dealing with this? Why is it not being degraded through the proteasome or the autophagy lysosomal system? It seems like there is a lot going wrong and it seems to involve fairly similar things, and I think that is something we can potentially therapeutically exploit someday.

Dr Tim Siegert:

There's a lot going wrong and there's a lot going wrong at different times of disease progression too, which kind of make it a three-dimensional question problem instead of just a two-dimensional question problem.

Dr Daniel Erskine:

Absolutely. But I think it's important that we embrace the fact that it's a three-dimensional question problem and not just focus on the sort of easier bits. And I think that's something that's really emerging from this meeting. I wasn't actually going use this talk, but it feels like a good opportunity to give my example and I'll do a shameless punt for my colleague and former supervisor, Johannes Adams, who gave a talk on mixed pathologies during here, and this is something he's really led in. My other colleagues at Newcastle like Lauren Walker have really played a prominent role in trying to understand mixed pathologies across the spectrum of neurodegenerative diseases. So yeah, this is something that I think is increasingly important.

Dr Heather Synder:

Well, maybe I'd go three-dimensional, actually maybe add that fourth dimension back to what we were talking about before when we add in that layer of resilience. So the three dimensions might be in terms of the neuro-degeneration and the progression, but that fourth dimension is a resilience component and where that figures in across the board, and I'm just going to skip into my next highlight and quickly with that, it seems like the right, just as you were saying, it seems like the right part of the conversation. I just had a really nice talk from one of the post-docs in there at Pascal's lab at University of Pittsburgh where they actually took the revised staging and diagnostic criteria that is a still in draught form and is in review at this point in time from an Alzheimer's Association work group. And then they looked at a population of about 160 individuals to say, where did people fit across their clinical and biological staging?

And it was really interesting. They had fairly high concordance within what you would expect based on the criteria, but then there was also the discussion around where resilience fits in and how we think about that. Comorbidities are also going to be part of that, and that will be part of the as you go and as you expand where you think about where it's vascular, where do some of these immune markers, et cetera, as we understand more and more about them. But that idea of resilience comes into play even as we think about that diagnostic, that diagnostic staging and biological staging is when people have higher resilience, they may fall into a, maybe outside of that particular path, they may have a higher biological staging, but a lower clinical staging. Because of that resilience, they're able to withstand more of the biological insult of the disease related changes that they're experiencing.

When individuals have lower resilience, they may not. This is of course, it was in only 160 people, which were across the 16 groups, so relatively small, but it does kind of open up the door to us to be looking at those kinds of questions. And then as we think about some of the mixed pathologies, as we think about some of those other measures, others biomarker measures, other P-tau measures, other vascular measures and beyond how we can actually get to that point of being very specific for the individual based on where they are in their diagnosis and what their anticipated progression might be and what their treatment path might be as well.

Dr Daniel Erskine:

Absolutely agree. And I think that this really does speak to personalised medicine to this idea that every person's on their own journey. There are a lot of similarities, but there are a lot of nuances as well across individuals, or between individuals and yeah, I totally agree and I think, but this starts with we target the individual bits first, for example, amyloid oligomers, and then we work out from there and work out and I guess ultimately become better at targeting each of these individual pathologies and it becomes a composite treatment that's tailored to the individual. It's an exciting thought.

Dr Heather Synder:

It's what we do in oncology. That's what we do in cardiovascular disease. These are complex diseases of a very complex organ. There's no reason that this wouldn't be the path that we would go. I think it's exciting. We've had our firsts, but we have work to do in terms of getting to our seconds and our thirds and all of those pieces together, not just for therapeutics, but diagnostics too.

Dr Tim Siegert:

Well, maybe I'll pick up there, because I thought yesterday there was a fantastic forum discussion led by Jeff Cummings and Howard Phillips upon innovation in Alzheimer's disease and how do you get new therapies through the clinical pipeline, right? So now that we know there's a finish line with the approval of Lecanemab, we have something that could potentially be part of a combination therapy one day. How do you increase the number of therapies that are tested in phase two? It's a really expensive undertaking. And then how can we get consensus around what's a meaningful phase two study response look like so that you can get interest from investors or pharma to show that you're having that potential to have a disease modifying therapy. And that goes beyond just biomarkers, which are a great tool, but I think biomarkers alone are a challenge. And how do you look at clinical endpoints of the disease or composites and think about how your creative in terms of starting to build that deeper phase two pipeline, so we have more opportunities and shots on goal to target different types of things, whether it's inflammation or neuro-protection or different ways to target tau or amyloid beta so that we can start diversifying our approaches to put more shots on goal for patients.

I think if you just barrel all in on anti-amyloid, you're going to get one answer. But if you can diversify, you really can get multiple answers at the same time, and you can only do so much pre-clinically that you just have to run the human experiment and find out,

Dr Heather Synder:

Well, it's a complex disease. It's not one biology. I think we've talked about that here, right? There's multiple biologies going on and we need to be addressing those biologies as we think about interventions and treatments for sure.

Dr Daniel Erskine:

I think actually that sort of, I suppose leads me on to another highlight of mine. It was a highlight of mine because, so I should say it was the Lundbeck phase two results for their MSA, anti-alpha-synuclein therapy. So this was a highlight for me because it's always nice to hear data from clinical trials, especially that that seems to be quite positive. I think what it really hammers home to me, and it is directly related to what you've just said, which is understanding what is clinically meaningful, and it's so difficult. I'm not a clinician. I sit in and I see differences between groups and I think to myself, what is clinically meaningful to the patient? I know this is a very difficult thing to define, and I know it's the subject of many, many debates, but it is something that I think requires some degree of clarity just to help us interpret these results when we see them. Because it does come down, I mean, obviously biomarker improvement is such a big thing. Imaging, which I guess is a biomarker, but understanding the clinical skills, the clinical instruments and how changes in them reflect real life measures, I think is something that really come out of that as being important.

Dr Heather Synder:

I mean, we hear from patients that what's clinically meaningful is that they want to keep doing what they want to do longer, and that may be very different for one person or another, but it's really in that earlier stage of when they want to be able to maintain independence in some of those other behaviors and functions and that how do you translate that to a test, to your point, is part of that challenge and measuring things that are meaningful to at the individual level, but on a population level or in a trial population.

Dr Daniel Erskine:

Maybe hat's the issue. It's the test, it's the problem rather than its interpretation.

Dr Tim Siegert:

Well, I think the clinical outcomes are not the most well developed. They're the tools we have at the time. But I think John Morris presented yesterday a little bit about clinical meaningfulness. Just if you get down into the weeds of what these scores actually mean in terms of if you can delay people by three years to the phase where they'd go from stage two to stage three and what that means for even just self-care and self grooming. Can people cook for themselves their own meals? Can they take care of themselves and wash and use the bathroom? That's where things get really meaningful and it's breaking the score apart from deeper down. What do those measurements actually mean within these composites, right? A sum of boxes you just think is a tally, but what do those individual pieces mean and what does it mean for when we now have therapeutics and when we're developing more for how long we could delay those steps?

Dr Heather Synder:

Well, I think, I don't know how many people in the audience yesterday, he made a joke in the beginning about his knowledge of CDR sum of boxes, and I don't know that it was completely lost on the audience that he is the developer of that. So that is, he didn't name it after himself. So people don't necessarily associate it. But there is actually no one better to talk about how those scores break down than John.

Dr Tim Siegert:

He did a great job.

Dr Emily Maguire:

He did, this has been such a great discussion because I feel like we've really moved from the kind of diagnosis and the biomarkers all the way through the basic biology back to the clinical trials and how we should be implementing them. So what a nice, well-rounded overview of the drug development process.

So on Friday we had our plenary by Ken Marek, and he talked about a biologic definition and staging platform for neuronal synuclein disease. And then on Saturday, we had one by Pam McLean, so that was this morning called Synergy in science, leveraging what we've learned about Parkinson's disease and Alzheimer's disease to inform Lewy body dementia research and therapeutic development.

Dr Heather Synder:

I've seen Dr. Ken Marek's presentation at a prior meeting or a similar presentation at a prior meeting, and I do think it was so much of what we've talked about even here, is this idea is that the underlying biology and how that defines or how that contributes to the progression to the clinical disease across the board and within, and Dr. Marek talked a little bit about this, that within Parkinson's disease, an individual clinically could have very different symptomology, but their biology is consistent or similar and why, or at least the biology that we can measure today or that we understand about today. And so how do we translate that to a diagnosis? And so this idea of neuronal cell nucleon disease or NSD, it was published about a month and a half ago-ish in Lancet, and it really sets this idea of biological staging of the disease, a biological definition of the disease, and allows us to take what we know today, but then also sets a stage to move earlier.

As we think about therapeutic development, as we think about clinical trials, it is very similar to what is happening in the Alzheimer's disease space. It's also what the Huntington disease community has done. And so as we think about that trajectory of defining the biology, thinking about that as we think about treatment, as we think about diagnosis across the board and getting to our conversation just a few minutes about comorbidities, that really you can start to move in that space where you can define and stage people based on where they have and hopefully better understand on a personalised way what may be contributing to their clinical symptoms. So I thought Ken did a really fabulous job of defining and explaining the work group's work in setting out the paradigm of neuronal cell nucleon diseases. It was really clear and great response. It seemed to be a great response from the audience.

Dr Tim Siegert:

Yeah, it's nice to have tools to be able to do that to define bio-pathology like cell nucleon, right where you now can try to measure and quantify at least positively identify people with cell nucleon disease through different techniques. It's not something really we had before. We just had clinical diagnosis.

Dr Heather Synder:

Like PET changed the game in Alzheimer's with our understanding of when those changes may have happened and even further than with CSF and now plasma. We're doing the same with some seeing assays and Parkinson's.

Dr Daniel Erskine:

I think it makes so much sense to have it based in the biology, especially with Parkinson's disease, where we always say that the area of the brain that's damaged determines the symptoms someone's has, but the pathology defines the disease. And this is so important for something like Parkinson's disease, because I work in a big metabolic centre. We get lots of mitochondrial disease patients, almost. There are particular mutations in mitochondrial gene, in nuclear mitochondrial genes that cause Parkinsonian features, that cause nigral degeneration. Is it the same as Parkinson's disease? Of course it's not because it's got a different aetiology.

Dr Emily Maguire:

We're almost out of time, but before we finish, I just have one more question for you guys quickly. So from what you've learned over the last few days, what excited you the most and what do you think is the next big discovery on the horizon? So just briefly, guys, so let's start with you.

Dr Heather Synder:

Yeah. I have to say that I think the thing that I've been the most just in awe and excited by is the energy and the collaboration and the environment, the ecosystem that we're in. It was great to see so many students and post-docs presenting throughout the week, presenting their science, but also really thinking and challenging the ideas and the questions and bringing in new perspectives. You made the comment earlier about immunology and neuroscientists, but I think there's more than that. There's also individual people that have vascular expertise, people that have metabolic expertise and more. And that has really been represented all week with the discussion. So while I don't know that I would say any one particular thing, I think more generally around, I think what gives me a lot of hope is that ecosystem that we're living in and really this multidisciplinary, cross-disciplinary, highly collaborative type of environment, and really that next generation of scientists that are clearly present in all corners that we're seeing them really come forward with presenting their work and moving it forward.

Dr Emily Maguire:

It seems as promising as it feels. We need to put it like that. Okay. So Tim.

Dr Tim Siegert:

That's great. For me, I think it's in terms of what the space has been like for so long, right now that we finally have our first FDA approved therapy for Alzheimer's disease in particular, we can start thinking beyond that, right? With new ideas, new creativity, not just in how to make those therapies better by getting more antibody into the brain or removing it faster, but thinking about orthogonal combinations in the future, keeping an open mind about ways to target the disease that isn't just so focused on amyloid over and over and over again and thinking more diverse. And now it's starting to bring these groups together that maybe at one point were a little bit siloed and at odds with each other. So building that community across different types of pathologies or disease mechanisms is really exciting to see.

Dr Heather Synder:

I like that. Building the community across the I like that.

Dr Daniel Erskine:

I have to say I agree with both of you. I think that it is the collaborative atmosphere. It is people challenging things before, but I think it's also open mindedness. But I think people are much less siloed now. People are much more willing to listen to alternative viewpoints, and that can only be of benefit to the whole field. Absolutely. So yeah, there is a great energy and I think that's what we'll take going forward, I hope.

Dr Emily Maguire:

Well, I'm sorry to say that that's all we have time for today. And yeah, the conference is just so big that there's no way we could have covered everything. But I hope these two podcasts have given you a peek into what's been discussed and that it's inspired you to check out some of the talks in the speakers online. So for now, I would like to thank our brilliant guests, Dr. Heather, Snyder and Dr. Timothy Siegert and Dr. Daniel Erskine. So I'm Emily McGuire, and you've been listening to the Dementia Researcher podcast live from the ADPD Conference in Midtown. Thank you so much.

Voice Over:

The Dementia Researcher podcast was brought to you by University College London with generous funding from the UK National Institute for Health Research, Alzheimer's Research UK, Alzheimer's Society, Alzheimer's Association, and Race Against Dementia. Please subscribe, believe as a review and register on our website for full access to all our great resources, dementiaresearcher.nihr.ac.uk.

END