Podcast – ADPD 2024 Conference Highlights – Part 1

Voice Over:

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

Dr Amanda Heslegrave:

Today we're going to be recording on location from Lisbon in Portugal. I'm going to share highlights from the first three days of this year's AD/PD Conference. This event brings leading experts together to unravel the mechanisms of diseases and to talk about the progress made on new treatments.

Hello, I'm Dr. Amanda Heslegrave and I'm a senior postdoc in the UK Dementia Research Institute at University College London. I lead a programme of work research to deliver fluid-based biomarkers for Alzheimer's disease but also all other forms of neurodegeneration. Now, joining me today, I have three more researchers and they're going to share their favourite talks in posters from the first three days of this conference, which is probably one of the biggest events in the calendar for neurodegenerative disease after AAIC. I'd like to introduce Dr. Ariana Gatt and Dr. Ian Harrison from University College London and Jess Tobin from Alzheimer's Research UK. So hi, everyone.

Dr Ariana Gatt:

Hi.

Jess Tobin:

Hello.

Dr Amanda Heslegrave:

We're going to start with a round of introductions and to give you guys a chance to talk about any research that you will actually be presenting this week. Ian, why don't you go first?

Dr Ian Harrison:

Cool. Thanks so much. My name is Ian Harrison. I'm a senior research fellow at University College London, and I work in the Centre of Advanced Biomedical Imaging at UCL. My lab works on the glymphatic system, which is this fluid clearance system in the brain, and particularly we're interested in the role the system plays in propagation of proteins. So alpha-synuclein and tau mainly and how it facilitates spread and clearance of those from the brain. So, this week, well yesterday actually, I presented a talk in one of the alpha-synuclein settings here talking about some of that work, sharing some of the data we acquired recently on an aqua flow inhibitor showing that it worsens the effects of alpha-synuclein propagation that maps flows.

Dr Amanda Heslegrave:

Fabulous. Thank you very much. Ariana?

Dr Ariana Gatt:

I'm Ariana Gatt. I'm also a senior research fellow at UCL. I work at the Tammaryn Lashley lab, and we are mainly a neuropathology lab, so we do a lot of ester chemical staining predominantly on post-mortem brain tissue. And my interest lies in RNA-binding proteins belonging to this family called hnRNP and their involvement in disease, more specifically frontotemporal dementia. So, there is a famous RNA-binding protein called TDP-43 which is very well known in its role in FTD, but we're more interested in it, what I like to call protein presence. So, the ones belonging to the same family but at the moment not as well studies as TLD. And I've got a poster in here looking at how this hnRNP family is altered even by single-cell RNA-seq data in different subtypes of frontotemporal dementia.

Dr Amanda Heslegrave:

Okay, thank you very much. Now, Jess, can you tell us about yourself.

Jess Tobin:

Hello. Yes. I am Jess Tobin. I'm the science communications manager for Alzheimer's Research UK. Obviously, I'm not presenting anything. This year I don't have any posters, but there's about five of us from Alzheimer's Research UK that have come over for the conference. As you mentioned, Amanda, it's really key conference in terms of neurodegenerative diseases and there are a number of quite large talks that we're expecting over this week. So, some phase 3 trials which could potentially get some kind of wider coverage. But then also a lot of our researchers are presenting and have posters. So, it is really great to come along to events like this. There's so much going on in the field and there's been a massive upheaval in the number of areas that are being investigated at the moment. So, each year, we come to conferences, it seems the programme is expanding so it's really fantastic to be here.

Dr Amanda Heslegrave:

Okay, thanks very much. With the introductions done, let's get to the highlights.

For anyone new to the podcast, let me explain the format. Now, this is quite simple. Essentially, we go around the guests three or four times, allowing them to talk about what they've seen, what has stood out to them, what they found most interesting, and then just give a summary and what they've taken away from that. So, I am going to go to Jess first this time.

Jess Tobin:

Yeah, brilliant. As I mentioned, this year is a really big year for Alzheimer's disease, in particular in terms of the first disease-modifying treatments starting to come through. Obviously, we've already had them approved in some countries like the US, but we're now waiting for the MHRA decision for lecanemab. And obviously for people affected by dementia, this is a massive turning point, and this is the first ever time we've been able to prove that drugs can modify or slow down the progression of Alzheimer's disease.

And so, there was a symposium hosted by the Alzheimer's Disease Drug Discovery Foundation yesterday in which our executive director of research and partnership, Susan Kohlhaas, sat on the panel. And that was a really fantastic discussion looking at the progress that we've made over the last 40 years, even within the last 10 years. When I started Alzheimer's Research UK just four years ago, the idea of having a disease-modifying drug seemed quite a way away and it didn't seem something that was tangible. And within the last year especially, it seems like there's just been this massive momentum and drive forward.

So, they hosted a fantastic panel discussion looking at the wider kind of therapeutic options. And as we know now, these removal drugs targeting mostly amyloid but also going into tau are now just a small proportion of the drugs that make up the pipeline. And Jeffrey Cummings later presented just after, and they were talking about how in his Cummings report, that just 25% of the drugs now in the pipeline target those amyloid and tau plaques and tangles. And so about 75% of those drugs are looking at other mechanistic areas. And so that was such a promising statistic for people affected by dementia and also in the wider field, especially when we're starting to look at a combination therapies and outcomes patients. So, it was a really fantastic overview of the wider field at the moment.

Dr Amanda Heslegrave:

Thinking about, you're talking about the disease-modifying treatments and how exciting that is. I think one of the highlights for me here is listening to people talking about how we then diagnose better and the possibilities of blood-based biomarkers, for example, which of course I'm really interested in, but also the care and attention that's got to be made so that we know what the biomarkers are telling us and that we use them in the right context. And I think that there's still quite a lot of... Well, yeah, there's still quite a lot of work to do on that, let's be quite honest.

Jess Tobin:

Yeah, exactly. And in terms of the fundamental research, we've come so far in terms of identifying biomarkers and seeing which ones hold the most promise and which work, especially in relation to gold standard like PET. But you are right, it's that integration into real-life communities and settings. And that's why things like the blood-based biomarker challenge that ARUK are launching with Alzheimer's society and NIHR, which we'll be looking at embedding blood-based and fluid biomarkers into NHS and real-world settings is within hopefully five years is really important.

Dr Amanda Heslegrave:

And then Ian, tell us... Tell us.

Dr Ian Harrison:

I'm going to go for one of the talks I saw yesterday moving completely away from biomarker stuff, but I felt a bit bad for the guy because it was the last session of the day, and you can tell that everyone was exhausted, and it was in a very stuffy room. But I thought the science was really exciting. So, it was from Li-Huei Tsai group at MIT, and it was presented by Mitchell Murdock who was a PhD graduate student in the lab. And what they did was that it was an animal study and what they did was that they exposed the animals to these 40 hertz sensory and visual stimulations. So basically, they put the animal in a box that flashed a light in its eyes and gave this 40 hertz frequency sound, and it caused this massive upregulation of the glymphatic system. When they did this in mice models of the FxFAD mouse, which an amyloid model, they saw a reduction in the amount of amyloid that was accumulating in their brains just from exposing the animal to a flashing light and a sound.

The paper was actually published last week in Nature. So, it's the first time that the work has been presented at a conference because they haven't presented it until now. But yeah, it was a fascinating talk and they're looking a bit more about the mechanism of that. They'd identified a neuropeptide which is involved in that. They show that there's an upregulation after this multisensory stimulation. But it was a fantastic talk showing quite an odd therapeutic intervention and how that can have a massive effect in terms of just brain function and CSF dynamics.

Dr Amanda Heslegrave:

Has there been lots of glymphatic presentations at this?

Dr Ian Harrison:

Not too many. I think there's still a couple of posters I need to go and check out, but it is one of those fields where we're often spread about the different categories. So, I was in the synuclein talk. That talk was in an amyloid therapeutic session. So, they're kind of dotted around, but if you look for them, you could find them.

Dr Amanda Heslegrave:

You need to find exactly where your hook is and get in there. Okay, then shall we move to you, Ariana?

Dr Ariana Gatt:

I'm going to link onto what Ian just said. I was at an A-beta session yesterday as well and there was a talk by Andre Obinous from Univerva in California and this really interesting study, I thought. I'm quite into this whole traumatic brain injury field and how it links to neurodegeneration. And so, they gave this talk where they had these juvenile and midlife mouse models of TBI. And what they found is that even in early on, juvenile traumatic brain injury incident can cause Alzheimer's-like changes much later on, which is really interesting. Behaviourally, cognitively they also see similar changes in the cerebrovascular staging and vascular uncoupling. And what's interesting is massive disruption of the blood-brain barrier similar to what you see in Alzheimer's disease, but in these juvenile mouse models of traumatic brain injury. So, I thought was quite interesting.

Dr Amanda Heslegrave:

Okay, all right. Well, I'm going to talk about, well just briefly, the plenary, one of the plenary lectures I really enjoyed on Tuesday, which was the genetics of neurodegenerative diseases and that was from rare populations to common variants and that was Rita Guerrero. And actually, I do know her, she used to work at ION. And I think the thing about her work that strikes me is that by looking, so looking at something that doesn't seem even related to what we're doing, we're doing macular disease and TREM-II. Then you find, okay, there's dementia in this disease. Could it be? Oh yes, it is. It is actually a risk factor for a very common disease which is sporadic AD.

And I think that the amount of information that we found from studies, the ones that she does with the different kindress, etc, is it is invaluable to, and it will be invaluable moving forward for the rarer diseases still that. Or when we try to put together a complete risk score to add to a screening programme for example, each one of your variants adds up to something and that leads you then to perhaps take that, not statin, but brain statin, that's what I'm going to call it, a brain statin, so that we can protect ourselves before anything even goes wrong. So, then we'll move back to Jess some further one.

Jess Tobin:

So, to add on to your summary, Amanda, also one of the plenary lectures on Tuesday, hopefully I didn't butcher the name, Henne Holstege and from the Netherlands. So, she is doing the 100-plus which is looking at the centenarians who remain cognitively healthy. And I thought it was such a fascinating take and a way to do one of these longitudinal studies because I think a lot of them which work with humans and are clinical trials are usually looking at disease pathology and what goes wrong. And it was quite nice and refreshing to have us study looking at what goes right and some of the findings that are already coming through confirm some of the beliefs that we hold around risk production messaging. So, a lot of them didn't smoke as much or had increased levels of exercise and social attainment and all these other things. But then there were also some really interesting factors that they pulled out. They had a greater sense of optimism, which I thought was really sweet.

Dr Amanda Heslegrave:

Smile.

Jess Tobin:

Sure. Yeah, exactly. And they pulled out and of, I don't know if any of you went, but they pulled out some of the quotes from some of these centenarians at the end and they had some really hilarious life advice like don't date too many men and all of these other factors, which I thought was a really, I don't know, upbeat and positive way of looking at research when a lot of these studies that we're looking at unfortunately a lot of the time are we are working with people that are really severely affected and it's obviously a really devastating condition for a lot of people.

So, I thought it was a really nice lightening topic. And I think the theme of ageing is running through this conference quite a lot and Miranda or yesterday and with the symposium spoke about these senescent cells in the body which are damaging and the possibility of if we can clear these weight potentially in people's thirties and reduce the significant effects of ageing, that we can try and prevent a lot of these things that go wrong downstream. So, I just thought, yeah, I thought she gave a fantastic presentation, and it was really reach cheerful, I thought.

Dr Amanda Heslegrave:

One thing that struck me about the Henne Holstege talk was the socio-economic status. That was an important factor that they all did not come from deprived families. So that was one thing.

Jess Tobin:

Yeah, we are seeing that a lot, especially with Lancet. So, the 12 modifiable risk factors, a lot of these things like education, educational attainment, the things that affect early on, they have links and socio-economic factors and so that's something our policy team are working quite closely with the government on.

Dr Amanda Heslegrave:

If you boil it all down to something, it was that they had less genetic risk factors and more protective genetic factors. So, there's a certain amount of luck there, I think.

Jess Tobin:

I entered this really fantastic slide looking at how your genetics influence your overall health. And I've written it down, so I didn't forget. They said something like roughly 20% of your genes you're reliant on when you are about 60, and that increases to about 70% by the time you reach 100. So those lifestyle effects do have quite severe implications, but as you get older, they start to drop off and you do rely more on your genes. So, there is that real necessity for gene targeting as well.

Dr Amanda Heslegrave:

And they looked brilliant as well, didn't they, in their photos? I wouldn't have even said 80s like they were saying. I was going more 70s, and I could only hope. And then I think we move back to Ian to see what more you've got for us.

Dr Ian Harrison:

Another talk I wanted to highlight was selfishly it was in my session, but I thought it was the speaker before me, Maria Spillantini, who everyone probably knows from history with alpha synuclein and tau and everything, but her lab has been developing this new animal model. So, she's particularly interested in synuclein propagation and how the potential for it to move from the gut and starts to accumulate in the epithelial cells of the gut, move up the enteric nerve into the brain. So, they've developed this new animal model where the animals express the 1 to 120 forms of alpha synuclein but is driven by a promoter which is only expressed in the gut endothelium. So, these mice only get alpha synuclein in the cells of the gut and then their group's starting to study its travel up into the brain from via the vagus nerve and doing some vagotomies and things to see how that root is affected if it's lateral or contralateral.

Really interesting stuff showing the primary root that alpha synuclein starts to seed in the brain and then they see once it's there, then it spreads to other areas that are synaptically connected. But it was a really lovely. We are used to seeing the similar animal models, especially in my field, in the propagation field where you induce with a prion-like promoter or a prion-like protein. But it's nice to see that there's still movement in the animal model development this stuff. And it is really nice at the end she was saying, "We want to give these mice to people. If you want to collaborate, if you want to use them, let us know. We will send them."

Dr Amanda Heslegrave:

I actually think it's incredibly brave to set out on a project to make a new model doing something that's quite different and then wanting to share it. I realise that that's written into a lot of grants now that you have to share the materials that you make and that's right, that's only right, that money should go to do that. But making something completely new that's going to be useful to the field I think is a real bonus.

Dr Ariana Gatt:

Yes. I am going to move back to the resilience stock for a tiny bit. I didn't actually go to the plenary yesterday because I was at another session, but this morning I did go to the resilience session and it was a really great uplifting way to start the day, positive news, as Jess said. I heard there was a talk about this 100-plus project. I did notice something. I don't know if it was statistically important, but a huge part of the cohort they have is female. I don't know if they... Did you guys notice that?

Jess Tobin:

Oh, I noticed that.

Dr Ariana Gatt:

72% is female, which is interesting. I didn't know if this was discussed yesterday in the plenary, but it's interesting because also we know that maybe there's a female correlation to more Alzheimer's disease probability. So maybe it is something about a switch.

Jess Tobin:

Yes. But yes, but women have longer life expectancy. Exactly, yeah. I'm general. Yeah, it is a weird relationship.

Dr Ariana Gatt:

It's true. But yeah, I thought that was interesting. But there were loads more talks in that session that were amazing. And I think a lot of that talk that was a common thread throughout was the inflammation aspect that potentially what happens in these super healthy centenarians, or the resilient population is they might have as much amyloid load, but then the inflammatory response different to a level that is protective active.

And the last talk of that session was by Beth Stevens from the Broad Institute, and she discussed this highly deeply phenotyped Finnish cohort, which is a brain biopsy life cohort. So, it's a sort of... Yes, it's amazing. So, an early Alzheimer's disease staging cohort and they're doing lots of omics on it. It's obviously a single cell RNA-seq data, bulk-seq data. And again, it's mainly microglial study that they're looking at. But one thing that I did pull out from it that was mentioned yesterday actually by another talk by Andrew Octavian-Sasmita from the Max Planck is that there seems to be a thing now that oligodendrocytes produce beta amyloids, which yeah, so in a lot of single cell data they seem to be picking up that oligodendrocytes have a high amyloidogenic gene expression, which is quite interesting. And quite new, yeah.

So, I think it's cool at AD/PD where yes, there's obviously the biomarkers and what's happening in the clinic, but what's really from a fundamental biologist point of view is to pick out these things that are fairly new that in the future will be.

Dr Amanda Heslegrave:

And one of the things you're talking about resilience. It does come up a lot in what we do is why do the people who have lots of amyloid, some people who have lots of amyloid, why do they not get dementia? Why are they spared? But also, it's really important in the world of disease-modifying therapies. Why would you give someone a drug they don't need? How do you know they don't need it? It's something that's going to be a massive question.

Jess Tobin:

And that's quite interesting. The talk that was just on the symposium hosted by ESI which Jeffrey Cummings spoke at, he was talking about what is clinical meaningfulness for people diagnosed with Alzheimer's disease and going into clinical trials especially. And there was a really interesting slide in which they highlighted the difference between FDA approval in America and EMA approval in Europe in which they said that, so do you know aducanumab was approved by the FDA, but it was not, can't think of the word, not approved by EMA. And that was because the FDA had criteria where they would accept biomarker diagnosis in lieu of clinically significant cognitive impairment. So, for people that showed positive amyloid clearance on PETs, that means that they approved that drug as clinically meaningful, whereas the EMA would not accept biomarker testing in lieu of any kind for pre-symptomatic patients. And so that's a really interesting point that a different government and government bodies and agencies will have different kind of criteria around what they accept as clinically meaningful.

Dr Ian Harrison:

It was a fascinating talk too from a lab, basic fundamental scientist point of view seeing... Jeffrey Cummings went through the numerous different cognitive scores and all of the different scales that you read about in papers, but he talked through them and said, "This is what this one highlight. This one is particularly sensitive to MCI," for example. And you don't... From my point of view as an animal scientist, I don't know these things, but it puts the papers that I read and when you read about the clinical trials' data, it puts that into a bit more perspective.

Dr Amanda Heslegrave:

Yeah. And I think that maybe there needs to be more education for all of us on what those papers mean because it is quite hidden sometimes what the meanings and we can't really interpret them. But I think mean for biomarkers, it's absolutely crucial. But also, what's crucial I think is the drug of the people who run the trials making the samples afterwards available to everybody else, not just their results, but what those are precious samples of people who've been treated with drugs that could tell us a lot of more information. It's probably not in the remit of what I'm doing here, but something that I feel quite strongly about.

Dr Ariana Gatt:

I've also seen a couple of posters that I think are interesting with regards to, and I think this is a field that we should be more open to discussing and looking at, is the effect of medication on the transcriptome in the body and that could be senior protective or harmful. So yeah, I think that's really interesting. And even this morning there was a talk by Howard Phillips who was discussing ageing and dementia and he's the chief scientific officer of the Alzheimer's ADDF. And he was talking saying about how now 40% of AD medication is actually repurposed drugs and 40%, which is amazing. And he brought up metformin, which is as we all know, an anti-diabetic drug but has these amazing neuroprotective effects that nobody's really looked at, maybe delved in as much.

Jess Tobin:

So, there's a lot of research at the moment, especially in the Parkinson space and AD looking at the, is it the G1P1 agonists?

Dr Ian Harrison:

Yes.

Jess Tobin:

So that's similar to-

Dr Ian Harrison:

Saxenda.

Jess Tobin:

Yeah. So yes, Saxenda and all those other things, Wegovy and all the Ozempic, the weight loss drugs, they're thoughts have major protective effects.

Dr Amanda Heslegrave:

Is this via their effects on metabolism?

Jess Tobin:

Yeah. I had an interesting titbit the other day. They might have to fact-check this, but apparently, they found, and they started finding these drugs because there's a lizard that exists that only eats once a year and they were like, "How can it maintain blood sugar? Why does it not die? How does it modulate insulin and all these other things?" And they found it had a really high number of these G1P1 receptors. And so, then they started looking at agonists for these receptors and they developed these group of drugs, which now is diabetes drugs but they're looking to have loads of other effects. And as we know, glucose metabolism goes quite wrong in a lot of neurogenetic diseases. So, it's a really interesting area of science at the moment.

Dr Ariana Gatt:

They might have a factor on vasculature and all of these things. It's so multifactorial. But yeah, I think it's amazing.

Dr Ian Harrison:

I think, yeah.

Dr Ariana Gatt:

Does anyone want too just... There was a really fantastic talk. So obviously ARIA, so amyloid related imaging abnormalities, is a big area of discussion at the moment, especially when looking at these amyloid targeting drugs like lecanemab and donanemab coming through, especially as ARIA unfortunately seems to affect people with APOE e4 status the most. And obviously their population that are more at risk of late onset or sporadic Alzheimer's disease. And up until very recently, I mean even now, the mechanisms of why ARIA happens aren't fully understood. And Donna Wilcox, so she's based at the Indiana University School of Medicine in the US, did some studies and proposed a kind of novel mechanism as we all discussed inflammation and immunity is a really big topic this year and it all seems to relate back to that. But she proposed a really novel mechanism around the complement system. And so how the anti-amyloid binds to amyloid beta in our vessel walls, which then allows the C2 complex to form and membrane attack complex and triggers those downstream inflammation processes.

But then she also proposed that it's possible that apiary has a role in binding to C1. And so, if it's a healthy version of APOE and that could more actively bind to C1 complex, but if those that have APOE e4, it doesn't bind as readily, potentially meaning that they have much more inflammation and much more ARIA in the brain. And so that potentially has massive therapeutic implications in terms of being able to develop these drugs for everyone affected or people with APOE e4 status. So, it's really exciting that she was part of a number of talks looking at potential ARIA mechanisms and considering we've only kind of had these drugs around and done these trials in the last couple of years. It's incredible the speed of science nowadays and how quickly these mechanisms are being investigated and proposed. And so, I thought, I just thought that was a fantastic talk.

Dr Amanda Heslegrave:

The whole ARIA scenario is really important and the need for some sort of test or indication of who we need to monitor more carefully who shouldn't get the drug because it will be really bad for them. I think those things are really important. But the thing about the science speeding up, I honestly think that COVID showed us how quickly it can move when it has to, and now we've got disease-modifying drugs. I feel like the whole field has been-

Dr Ian Harrison:

Sped up on the-

Dr Amanda Heslegrave:

Yeah. And it's great and I don't think there's anything wrong with how we were working before, but I also think that when you can't see that we are able to do anything, it is much harder to have the momentum. And I feel like we've got it now.

Dr Ariana Gatt:

And the technologies. So now it's amazing for me to look at these posters, everyone doing single-cell and everyone's going more on AC and that's great because that's data that's available to everyone and we can all compare and contrast. And it also makes science more global, I feel, because you can compare the effects that are happening in say, cases from the US compared to other countries and we can all sort of just-

Dr Ian Harrison:

By sharing data.

Dr Ariana Gatt:

... harmonise easily. Yeah, exactly. I think that that'll be clued to finding eventually disease-modifying therapies as well.

Dr Amanda Heslegrave:

I think yeah, at that point, probably the other plenary that was on a Monday that was really good, but I'm not going to claim to be any sort of an expert was, hang on, Koichi Tanaka who I listen to from... He's Japanese, but he's a Nobel Prize winner and has done amazing things with mass spec technology and developed lots of things I can't explain really. However, I have used mass spec and it's a very useful tool for discovery sites. We wouldn't know half of the proteins that we look for now without mass spec, but also, it's really useful and we do use it for targeted identification of proteins as well where some proteins are just impossible to find with antibodies or very well, and we can use targeted mass spec. And so, I don't really know what he got the Nobel Prize for, but I'm sure it was really good. I don't know if anyone else went to the cryo-EM structures of disease because that the fact that structures can be just slightly different for different diseases is a bit. But what did you think?

Dr Ian Harrison:

So yeah, like you said, it was the plenary yesterday from Michel Godin, he was talking about tau, well, cryo-EM-resolved structures of tau and alpha synuclein and amyloid in various different forms of neurodegenerative disease. So, what was quite nice is that, so Michel's group at the LMB published this work, the first tau structure maybe about a decade ago, something like that, five years maybe. But what I really liked about his talk is that he was showing the slowly increasing N number saying we've done 12 pure Alzheimer's patients. Now we've done another six parts of this.

Jess Tobin:

It depended on brain donation, the process.

Dr Ian Harrison:

Exactly. Because in one of the original criticisms of their work was that it was an of 1. There was a brain sample and cryo-EM structure of tau was resolved, which was fascinating. But there's still that question is one, but it was really interesting seeing how he was stratifying all of the protein classes and the different folds and how they slight changes means that you have a completely different way that that protein builds up in Pick's disease, for example, rather than all of the rarer neurodegenerative diseases. But they share this common mechanism with a protein accumulation. Yeah, fascinating. Yeah, really good.

Dr Amanda Heslegrave:

So, has anyone else got any other highlights, particular highlights? Even just about the conference, not about a talk or anything?

Dr Ariana Gatt:

Yeah, I just found again the resilience talk this morning really, really, that session was amazing, I thought. There was another talk by Bradley M. Hyman from the Massachusetts General Hospital, and they showed this amazing finding. I thought that they had these tangle-bearing neurons compared to non-tangle-bearing neurons in vitro and that the non-tangle-bearing neurons have higher risk of dying than the tangle-bearing ones. So, there's the protein.

Dr Ian Harrison:

Wow.

Dr Ariana Gatt:

So there, well, he wouldn't say, I'm saying that a tangle is a good thing, but that potentially sort of the more fibrillar form is potentially-

Dr Ian Harrison:

So, the type of protein.

Dr Ariana Gatt:

Yeah. The non-tangle-bearing ones are more at risk of dying three times more, something like that.

Jess Tobin:

Yeah, I thought maybe 30% or 6 to 3, that's the thing.

Dr Ariana Gatt:

There was a three somewhere. But he also showed something which I thought was very interesting, is that one to two weeks before dying, these neurons show a slight shift in... They swell so slightly that their neighbouring neurons move a tiny, tiny bit and that is insinuating that neuron is about to die. I just thought the whole microscopy imaging weight, it was just amazing. Yeah, really fascinating step.

Jess Tobin:

There was one other talk by Markella Lund from the University of Ontario, Canada, Ottawa. Ottawa, yes. I can't read my own writing. University of Ottawa, Canada. So, she was looking, this was on yesterday, she was looking at nasally acquired viral infections in mice studies and whether they impacted risk of neurodegenerative diseases. So, I believe most of her work is based in Parkinson's, but then there was some application to tau and phospho tau, which is why she was speaking at the tau talks yesterday. But I think this is quite an interesting area for in general the public because there's a lot of talk at the moment around COVID and things like brain fog and we don't quite understand yet what that relationship was. And obviously massive caveat, this is in mice, and it was looking at, so it looked at VSV and so H1N1. So H1N1 Was the more kind of the peripheral lung type virus.

And what was really interesting is they introduced these viruses to the mice and then those that survived, they waited six weeks to see whether there was any kind of phospho tau in the brain. And they found for both VSV and H1N1, that there were significant levels of phosphorylated tau compared to no virus in the mice after six weeks showing that there could potentially be some quite significant long-term neurological impacts from acquiring a virus. And so obviously this is very early research and it's in mice, but this kind of research is really important in us starting to understand the long-term implications of viruses like COVID. So yeah, I thought it was a really fascinating talk.

Dr Amanda Heslegrave:

But also, we acquire infections throughout our whole life. How much of that then appears in our brain as amyloid or something later? How much? We don't... There's not a lot we can do about colds and stuff like that, but there will be a certain amount of damage left behind.

Dr Ariana Gatt:

We do now know that again from RNA-seq signal cell data that you do get a lot of viral gene associated pathways are regulated in a lot of neurodegenerative diseases, which again, those to show there's a link there. So that's interesting. Something that I assume again will be looked at more and more in the future.

Dr Amanda Heslegrave:

Question to all, and we'll go round 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? Ariana first, please. I'm going to put you on the spot.

Dr Ariana Gatt:

Thanks for that. I think as a fundamental biologist, I do think that the larger cohorts of data that we're getting is quite exciting. All the omics that is happening, all the RNA-seq data that we're getting that again will allow for greater collaboration and for finding these little maybe thus far hidden and factors that are involved in neurodegeneration that will create more and more momentum into looking at maybe avenues that haven't really been explored yet. Maybe this viral infection or the fact that maybe it's not just about neurons making beta amyloid, but there's other cells involved in the brain. I think these are the things that excite me the most about conferences like AD/PD.

Dr Amanda Heslegrave:

Okay. Thanks very much. Ian.

Dr Ian Harrison:

I think one of the talks that most excited me was that glymphatics talk that I mentioned, and I think it's one of those fields which it is been in the periphery of neuroscience for a while, but is now starting to play more of a role in conferences like this and in Alzheimer's disease that disease researchers are starting to come aboard and look at this pathway in the brain in terms of what I think the next big discovery is, I don't know, I think something along the lines of... There's all of the kind of phase 3 data and all of those trials' data which are now delivering. I think from my perspective, I would really like to see some movement in the lifestyle changes as being testable and tangible things that can be put through trial to see if they have any tangible effect, details of reducing the burden or progression.

Dr Amanda Heslegrave:

Something achievable. Brilliant. Jess.

Jess Tobin:

Obviously, amyloid has come on, anti-amyloid drugs to come on massively. And we're now waiting on, like Ian said, phase 3 trial data from TauRX. But I think from what I've seen so far, what Ian mentioned earlier about that gamma radiation, the 40 hertz clearance, but then also some of the, so there's some small molecule drugs in development for TRM-II, and it's these less invasive potential treatments that are potentially coming through, which will allow us to deliver combination therapies. So, the lecanemab and donanemab potentially great for a very small subset of people and they only have a modest effect. And if we're to develop disease-modifying treatments for much more of the population and we need those combination therapies. And so yeah, I think there's a lot of promise and a lot of different areas in the programme. It's really exciting.

Dr Amanda Heslegrave:

And so, I'll finish with mine then. I think the fact that we're talking so much about the blood biomarkers and how we use them is really exciting because I think that we've got some that are good enough to use already if we get the context and the standardisation collaboration to make sure that there is a consensus. I think that that's really exciting.

And I think the next big thing, I hope the next big thing is that a tau therapy works and maybe in combination with an amyloid therapy proves to be more benefit. Because we know amyloid drugs are beneficial. And to a patient or their caregiver, that might be really important. But if we can up that, I think that that would be kind of really, really exciting. So that's what I'm looking for in the next year.

Dr Ian Harrison:

Each care that did it.

Dr Amanda Heslegrave:

I know there's a talk that.

Dr Ian Harrison:

A thought.

Dr Amanda Heslegrave:

I'm just going to go through. I'm really hoping then that I can be right. But anyway, thank you so much. But that's all we've got time for today now. So don't forget to tune into part two for highlights from the rest of the week, which we'll be filmed very soon. But for now, I'd like to thank our brilliant guests, Dr. Ariana Gatt, Dr. Ian Harrison, and Jess Tobin. I'm Amanda Heslegrave and you've been listening to the Dementia Researcher podcast live in the AD/PD Conference in Lisbon.

Dr Ian Harrison:

Tobin.

Dr Ariana Gatt:

Bye bye.

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 and leave us a review and register on our website for full access to all our great resources, dementiaresearcher.nihr.ac.uk.

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