Podcast – ADPD Conference Highlights 2022

Voice Over:

Welcome to the NIHR Dementia Researcher Podcast brought to you by dementiaresearcher.nihr.ac.uk, in association with Alzheimer’s Research UK and Alzheimer’s Society, supporting early-career dementia researchers across the world.

Katy Hole:

So, hello, and thank you for listening to the Dementia Research Podcast. This week, we are recording on location from the AD/PD Conference in Barcelona, where the weather has been poor, but the science has been great. I’m Katy Hole. I’m a fourth year PhD student at the University of Bath. And after one too many drinks on Wednesday evening, I volunteered to be the host for today’s show, so here I am. Of course, as ever with these conference highlight shows, we have an amazing lineup of guests to share their best bits, which definitely takes the pressure off of me. So let’s introduce them. First of all, we have two people who know a great deal about biomarkers, which is useful as that’s been a hot topic this week. So I’m delighted to introduce Dr. Amanda Heslegrave from University College London, and Wager Brum from University of Gothenburg.

Dr Amanda Heslegrave:

Hi, I’m Amanda, and I run the fluid biomarker laboratory at UCL in the Dementia Research Institute. We work on collaborations mainly with lots of different groups all over the world, well, to measure your cohorts for the biomarkers of interest.

Katy Hole:

Great. And Wager?

Wager Brum:

Hi, I’m Wager. So, I’m a joint PhD student between the Federal University of Rio Grande do Sul in Brazil and the University of Gothenburg in Sweden, where I’m currently working. So, I’m mostly working with plasma biomarkers of Alzheimer’s disease, and I’m very much interested in understanding how they link to AD pathophysiology with patent and postmortem data, but also to address the challenges that we must understand before they go into clinical practice, such as biological variation and other factors that might affect biomarker readings.

Katy Hole:

Nice. So next up, coming all the way from Chicago, we have Dr. Percy Griffin, who is director of scientific engagement for the Alzheimer’s Association. Hi, Percy.

Dr Percy Griffin:

Hi, I’m Percy Griffin. As mentioned, I’m director of scientific engagement with the Alzheimer’s Association. So, in my role, I work with the over 75 chapters in the United States. I’m focused on advocating on behalf of the patient for Alzheimer’s disease to try and achieve our vision of a world without Alzheimer’s and all other dementia.

Katy Hole:

Awesome. Last, but by no means least, we have UCL PhD student, Anna Wernick. Anna is exploring lysosomal dysfunction in iPSC-derived models of Parkinson’s disease, which luckily for us has also been a topic covered at this conference. She also probably had the best tweet of the conference, so go check that out. Hello, Anna.

Anna Wernick:

Hi. Yes, I’m a second year PhD student at UCL, and I’m actually based at the Francis Crick Institute in Sonia Gandhi’s lab. In the Gandhi lab, we use iPS models from Parkinson’s disease patients. My project specifically focuses on lysosomal dysfunction. I’m especially interested in a gene called GBA, which is one of the greatest risk factors of Parkinson’s disease. The GBA talk is actually a bit later on today, so I’m looking forward to that, but there’ve already been lots of really interesting lysosomal talks that I’m excited to talk about here.

Katy Hole:

Yeah, I can’t wait to hear about that. So thank you all so much for escaping from the conference to join us on this podcast. So, for those who don’t know, these shows have a pretty simple format. Essentially, we go around the table, shamelessly plug our own talks and highlight our favorites from other people. For those who don’t know, the AD/PD Conference is mostly aimed at clinical and lab-based researchers. This year, it has over 3,000 participants, both in-person and online, from 64 countries and with 594 speakers and 839 posters. So there’s a lot to take in. So, Percy, I’m going to come to you first. What presentation has stood out for you so far?

Dr Percy Griffin:

Thank you. So before I get started on the specific presentation that has stood out to me the most, I just want to point out a theme that we are seeing all through AD/PD, which is the maturation of the field. So, in the past, things like Alzheimer’s and other dementias, pretty much diagnosing them was kind of a guess. We had what? About 30% of patients who are in clinical trials really not having Alzheimer’s pathology, but nowadays we’re at the point where we have blood biomarkers that can stage the disease. I know Wager and others are going to be talking extensively about those biomarkers, right? It points to such powerful progress in the field, as well as the approval of therapies that are aimed at targeting the underlying biology of the disease. Now, the fact that we’re at the point that we can even say that and think about that and its application in health systems is so important and for moving the needle towards what people need, which is powerful precision medicine in combination form, that helped change the course of the disease.

Dr Percy Griffin:

Now, with that giant grant standing done, I want to talk about my favorite talk so far, that was a talk by Michael Heneka. His talk focus on the cellular interactions of microglia neurodegenerative diseases. A lot of times I feel like we lose some of biology’s liveliness when we put up graphs or have flat images that don’t really show as much. This talk did not do that. So, in terms of the science, he showed that microglia form tunneling nanotubes with neurons. Again, back in the day when I was doing my PhD, we talked a lot about communication between different cell types in the brain. But here, he showed that not only do they form these nanotubes, but they can use those to transfer organelles between the microglia and the neurons.

Dr Percy Griffin:

Seeing this and how it becomes dysfunctional in diseases like Parkinson’s, it was super cool to see coming alive on the screen. I used to do a lot of neuroimmunology and imaging, so that’s my bias for that particular talk as well. But it also opened up other questions as to the importance of some of these cell-to-cell interactions in other neurodegenerative diseases. This was described in Parkinson’s, but what do we know about this in frontal temporal dementia and Alzheimer’s and all of the other biological causes of dementia that are yet to be explored? So, it was a very exciting talk to see, and I hope you can catch it on demand if you didn’t see it live.

Katy Hole:

Yeah. I sadly missed that one, which I’m gutted about.

Dr Percy Griffin:

Yeah.

Katy Hole:

But yeah, it’s really cool that this tunneling microtubules, is that what they’re called?

Dr Percy Griffin:

Yep.

Katy Hole:

That they’re coming through. I remember when I was doing my undergrad, they were mentioned and then quickly dismissed as probably being a hoax. So it was really cool that they’ve managed to capture that live and you can really see that happening. Like you said, I think it’s really going to open up the field and this whole new exploration that they can do now. So that’s really cool.

Dr Percy Griffin:

Yep.

Katy Hole:

Nice. So, Amanda, let’s come to you next. There’s a lot of biomarker talk here, but is any of this new and what stood out for you?

Dr Amanda Heslegrave:

Yeah. I mean, I’ve mainly been to fluid biomarker talks at this conference, and anything strikingly new, I’d say no, there isn’t, but what there is is lots of progress, like building up the evidence that we’ve got, that these biomarkers in blood are actually effective and useful. I think that one of the things that I wanted to get from the conference is that confidence and that evidence for when people come to us and they say, “We want to do this study. What should we measure? How will we go about it?” And that’s kind of what I need to get here. I need to be able to say, “Okay. So I do realize that phospho-tau 217 isn’t available commercially at the moment, but I have an idea that it will be.” But I want to be able to say, “This is what the biomarker you need to use. This is going to tell you in your population what you need to know.”

Dr Amanda Heslegrave:

And the talk, just one of the talks I saw earlier today, actually, by Anthony Griswold from the USA, I didn’t actually get the University, apologies, he was talking about looking at phospho-tau 181 in individuals of diverse ancestral backgrounds. The reason why I really like this is because that’s one of the things that we miss and we have missed for a really long time, is that it’s all very well measuring these things in a European population, a white European population. However, that is not going to give us precision medicine for the whole world. This is going to give it for a tiny, for a proportion of it. I think one of the thing, I didn’t even know this, is that the APOE4 risk is so different across ethnicities. So that was something that was actually quite new to me. Maybe it shouldn’t have been.

Dr Amanda Heslegrave:

But also when you look at the genetic makeup, that actually it’s not as simple as that either. You can’t distinguish African-Americans. There’s a continuum between us all. We’re all related somehow, but we really need to look at what that relatedness means or that difference means when we think about diagnosing somebody or indeed looking when we get those drugs that we need, indeed looking at responses in different populations, because they’re not all going to be the same and we don’t want to treat the wrong person with the wrong drug. That’s the kind of thing. That’s my thing, right? The right person needs the right drug and we need to consider lots of things in that landscape.

Katy Hole:

Yeah, that’s so true. I think also it kind of goes against precision medicine, doesn’t it, if you are only looking at one population and then trying to treat a whole other population that might not have the same response.

Dr Amanda Heslegrave:

Exactly.

Katy Hole:

So, definitely something that needs to be considered going forward. Wager, I’ll come onto you next. Maybe have some comments on what Amanda said, and I know you’ve been presenting so you can tell us about that.

Wager Brum:

Yeah. I completely agree with Amanda’s view. I think that I’m also heavily biased towards fluid biomarkers, as I mentioned before. So I think that in 2020, we saw the beginning of these plasma phosphorylated tau assays. And that moment, we were all very surprised that we were actually to able to measure it in the blood. And then I think that last year, in the conferences from 2021, we saw, again, some information pointing that they worked, but it was still a little bit more restricted to some of the cohorts that measured it in the beginning. And I think that this year is really a year of maturation, like Amanda mentioned, because now, most of these assays are coming into commercial platforms. So, lots of people and lots of cohorts in different ways, even in more diverse backgrounds, as it’s much needed, are starting to measure them.

Wager Brum:

I think that one really urging question that showed up with the beginning of the plasma phospho-tau assays was that we had one paper talking about phospho-tau 181, another paper about 217. Maybe in the beginning, we were really thinking, “Well, okay, which one is the best?” And then last year, we had more, and this year we have data from even more different assays. So we are in a point in which comparisons are needed and quite a lot of studies now here in this year and this was something that we did not have so much in the past two years. We’re seeing lots of comparison between different plasma p-tau assays. It’s looking like sometimes it’s something that might depend more heavily on the assay and how the assay works, then maybe some special biological differences between phosphosites.

Wager Brum:

So I think that I’m pretty excited to see them being measured in so many different places and actually confirming that what we’re doing and offering to our collaborators is really working. I think that it was really also interesting to see the plasma p-tau discussion in light of the recent therapies. We saw some very interesting data pointing that plaque reduction was associated with… in the aducanumab trial was associated with changes in phospho-taus. So, it’s more evidence linking that phospho-tau might be an early event between amyloid and tangles. Well, I mean, it’s just been very interesting to see how well they are working and understanding our next challenges with the plasma p-tau assays.

Katy Hole:

Yeah, super exciting. I’ve got to say, I’m not an expert in biomarkers, but I’ve been in the field for three and a half years. When I first came to, I think it was the AI UK Conference, they were kind of talking about biomarkers as a what if this happens, or wouldn’t it be amazing if we had this in 10, 20 years? For it to have happened so fast and to have come so far in such a short amount time with a pandemic in the middle is kind of crazy and really exciting. You feel like there’s a buildup of something that’s good that it’s going to come really soon. So that’s really cool. Any other comments on that?

Dr Percy Griffin:

Yeah. I want to add real quick to some of what you guys said about the plasma biomarkers. The diversity angle that Amanda brought up is so important, not just because of driving access to underserved populations, but not understanding how these treatments or these biomarkers works in all populations is just bad science, right? For example, Michelle Mielke showed that people with chronic kidney disease, as well as cardiovascular conditions have changes in their plasma p-tau in the blood, which may limit the use of these biomarkers in those populations, and African-Americans in the United States are people who have higher incidences of these particular conditions, right? Just to add also to something that you said, Amanda, is you want to get the right drugs into the right people, but also at the right time, and that’s what these biomarkers are giving us as well. These blood biomarkers are giving us the ability to stage the disease and catch the disease at different stages to make sure that we’re giving the right therapies at the right time to benefit the right people.

Katy Hole:

Yeah. So true. So Anna, I’ll come on to you next. I know this is your first in-person conference, I think. Is that right?

Anna Wernick:

Yeah, the first one of my PhD.

Katy Hole:

Yeah. Which is crazy, in Barcelona’s pretty good one. So maybe you tell us a little bit about just your experience of the conference and how it’s been for you, and then what’s caught your eye.

Anna Wernick:

Yeah. So it’s been really exciting so far. I’m presenting a poster. So that’s been really nice to have people come up to me and to actually get some in-person feedback, which is nice. It’s been really useful far. I had a chance also to catch my colleague or my lab mates talk this week as well, which was just really exciting to see our lab in action. So I think it’s going great so far. Yeah, it’s been fun and even though the weather’s not been great. I’ve never been to Barcelona before, and I’m really enjoying it here.

Anna Wernick:

There’s been quite a lot of good lysosomal talks actually this week, especially in the context of Parkinson’s disease, which is my preference, my disease of preference, but one of the main ones, I think, springs to mind is Dr. Mara Samirani’s talk. She’s from France, and her talk was on the role of the lysosome in the seeding of alpha-synuclein. In her talks, she reported that alpha-synuclein fibrils are spread between cells in a prior unlike manner. She reported that this is occurring via nanotubes, which Percy just spoke about earlier. So it seems to be quite hot topic this week, because this was actually one of the first instances that I’d really had much about and I found it really interesting that whole canals can be spread through these tunnels, including lysosomes. And so, in her research, she found that in cells that were treated with alpha-synuclein fibrils, the cells took these fibrils up and localized them to the lysosome. And this damaged the lysosome, causing the pH to rise so it becomes less acidic and that the membranes became more leaky. So, the lysosomes were then more likely to transfer these fibrils.

Anna Wernick:

In some cases, she actually saw that these unhealthy cells that had taken up these fibrils and transferred them to their lysosomes. They were actually able to transfer their damaged lysosomes via these nanotubes to healthier cells that hadn’t been treated. And in return, the healthy cells actually transferred healthy lysosomes to these sick cells. So, she suggested that there seemed to be some kind of rescue mechanism, which I thought was really interesting. All her work focused on control neurons that actually treated with these fibrils, but she mentioned and I think it’d be really interesting that I think the next stage of this research would be to study this phenomenon and cells from Parkinson’s patients, which had specific lysosomal mutations, such as GBA. So I thought that’d be really interesting area to follow.

Katy Hole:

Yeah, it’s really cool. It’s good that you found your little niche here.

Anna Wernick:

Yeah.

Katy Hole:

So, for me, I think probably my favorite thing about being here is just being able to talk to people again. I feel like I never really got that network experience for a lot of my PhD and now I’ve just spoken to so many people. I found people from Europe, from Canada who do a very similar things to me and you can really collaborate on ideas and just sit. It’s good feeling. In terms of talks, I’m a tau person, so I really enjoyed the tau therapies talk in the first day. It was good for me because they didn’t focus on antibodies mechanisms, which is just clearance, which obviously is important, but I’m more interested in kind of mechanistic ones. They were looking at other mechanisms of targeting tau. One example was Suzanne Herzlinger. She showed that you can actually restore spine density in a mouse model of tau-T by over expressing soluble alpha APP using AAVs. I don’t know if that’s got a therapeutic potential, but it’s just really interesting.

Katy Hole:

Another cool one was by David Tempolini, who was looking at whether deep brain stimulation can ameliorate tau pathology and in neurons culture from a PS19 mouse, which is a tau mouse. They found a decrease in tau organism phospho-tau following LTP, and showed that synaptic stimulation promotes lysosomal degrading activity, which actually really interesting because people have been shown before that if you stimulate neurons, they propagate tau. So it’s interesting that you have this one mechanism where you stimulate them and the lysosomal function improves. They’re thinking that’s a therapeutic target, but maybe it’s also going to spread it around. So I think they need to look at that, but it’s quite interesting for me, maybe not for anybody else. Yeah. If we go around the table again, Wager, have you got any more talks that stood out for you?

Wager Brum:

So, still staying with my bias of blood biomarkers, I think that an interesting discussion right now in the field of blood biomarkers is whether we are going to have one biomarker or if we’re going to do a panel with several different biomarkers. So, Sebastian Palmqvist from Lund showed some interesting data on biomarker panels and there are also many other people who will show interesting work on that. Pamela Fejera from Pittsburgh is also presenting some interesting data on that today. Something that was caught very much my attention was during the plenary, in the biomarker planetary by Oskar Hansson, where he showed some new data with an alpha-synuclein ligand. I think that this is something that… I mean, we are in AD/PD conference, right? I mean, and I think that sometimes since we have some more tangible advances in biomarkers for AD, I think that we really, really need good biomarkers also for Parkinson’s disease. So, it’s very exciting to see some promising data on that.

Katy Hole:

Yeah. That’s really interesting. I didn’t go through that talk. But so did they find that they’ve got a marker that can detect in Parkinson’s disease? Because I know they’ve been saying that they had a alpha-synuclein marker that didn’t correlate with Parkinson’s disease before.

Wager Brum:

Yes. Yes. So, he showed a preliminary data from a smaller subset of patients, but it really seemed that the tracer seemed to be working in individuals with Parkinson’s disease in comparison to controls and individuals with AD dementia. So, it’s very interesting, and I guess now we’ll have just to wait to see more data on that.

Katy Hole:

Yeah. Hopefully we will. If it’s anything like the p-tau, I think it hopefully will go quite quickly. So, should we go to Amanda next?

Dr Amanda Heslegrave:

I guess. Yeah. Just carrying on from that, sorry, did they do pathological tau measurements in the CSF for that one? I did see it. I can’t remember.

Wager Brum:

For the alpha-synuclein ligand?

Dr Amanda Heslegrave:

Yeah. I just wondered.

Wager Brum:

I’m not really sure. I don’t think he showed AD fluids for the synuclein ligand.

Dr Amanda Heslegrave:

Because, yeah, one of the things that, I mean, we know where there are holes in our arsenal, we don’t have really good, easy-to-use alpha-synuclein methods to measure that in fluids. I know that there’s a quaking assay, which I haven’t actually heard anyone talk about here. There might have been someone. There’s so many talks. You just can’t go to everything you want to, but that’s the way of it. But also, TDP-43 as well is another thing that we really need those assays, for which I’ve been… There might be one on there actually, while we’re sitting here, to be honest. But no, I watched Oskar’s talk and that was all very… I mean, the BioFINDER cohorts of are really great cohorts, I think. The longitudinal stuff that he presents is also really good. So, that was really interesting.

Dr Amanda Heslegrave:

I think Nick Ashton’s talked today talking about measuring in real-world scenarios, I found that really interesting because a lot of studies are presented to you having been picked and all of the people that will cause you a problem with your analysis taken away, taken out of that study, which is how you start. That’s how you have to start to get meaningful results, but actually then taking it and measuring the next person that comes to the next one, the next one, the next one is the way that you see if it actually works in a real-world situation, which is with the plasma biomarkers is definitely where we need to be going. Otherwise, we’re never going to.

Wager Brum:

Yeah. I think that it also goes in line with what you and Percy were discussing before, because I mean, we already have this population, this ancestry bias on the populations that we look the most in North America, in Europe, but even within these settings, sometimes we are also still much restricted to very specialized dementia cohorts. So this talk, I think that this is also one of my highlights. So, this work that Nick Ashton led in collaboration with Marc Suárez and the Hospital del Mar. I’m not going to say Hospital del Mar. I’m not sure. I always get confused if it’s Sant Pau or Hospital del Mar. Okay.

Wager Brum:

So yeah, this talk by Nick Ashton about his work that he led with the team of neurologists here in Barcelona, Marc Suárez, and his other colleagues, it’s really interesting because I mean, within our mostly European and north American settings, we are needing much of these works that focus beyond these specialized dementia cohorts. So this was a very heterogeneous memory clinic population, in which they collected paired plasma and CSF. We just saw that the biomarkers seem to work very well to detect underlying AD pathology. I guess that we really need to look beyond these specialized dementia cohorts in our own settings.

Katy Hole:

Yeah, sure. Percy, anything more?

Dr Percy Griffin:

Yeah, I can add a little bit to what Wager and Amanda were talking about here. So, the importance of getting all of these biomarkers for alpha-synuclein and tau and amyloid, and even TDP-43, is that over 50% of the cases that present in the clinic are mixed dementia, right?

Katy Hole:

Yep.

Wager Brum:

Yeah.

Dr Percy Griffin:

And that kind of points to some of the work that Betty Tims was talking about in that there are several molecular subtypes of the disease, right? And if you want to move towards precision medicine approaches, you need to know what pathology is happening in who to make sure that the drugs that you’re delivering works in the people that you’re giving them to, and having all of these tools at our fingertips is going to help us do that. So that was just adding to the biomarker discussion, and now I’m going to go to my own bias, which is the neuroimmunology discussion once again, and these were two fascinating talks that I’m going to merge together.

Dr Percy Griffin:

So, one was by Bruce Lamb, who is at Indiana University, and the other was by Oleg Butovsky, who is at, I believe, Harvard, but don’t quote me on that one. Again, part of the maturation of the field is that the diversity of targets that we have begins to grow, right? More and more, you’re seeing people talking about the impact of the immune system on disease pathology. I know back in the day, again, I don’t exactly remember when, but there were trials that looked at nonsteroidal anti-inflammatory drugs in Alzheimer’s disease, because if the immune system is causing the pathology, just turn it off, but that didn’t necessarily work because there’s greater nuance than that. And that was the work that Bruce Lamb showed. So, he was looking at PLCG2, and he showed that in one genetic form, in one genetic isoform of it, it was protective, and in the other one, it was, it was detrimental. It’s the same risk gene expressed in the same cells, just pointing to the level of nuance that is required to fine-tune the immune system to provide real benefit to people living with the disease.

Dr Percy Griffin:

Oleg Butovsky was doing something similar too, because he found that in a APP/PS1 mice… Of course, we all know APOE. APOE4 has been painting at as this bad guy who always goes wrong and increases your risk for developing Alzheimer’s disease, but he showed that APOE4 microglia, whereas they promoted astrocyte and microglial activation in the brain. In the eye, APOE4 microglial were protective. So, we need to ask these questions about how do we fine-tune these systems to ensure that what we’re doing to modify or change the disease course is actually beneficial to the right people.

Katy Hole:

Yeah. Great. Anna, anything more?

Anna Wernick:

Yes. There was another lysosomal talk, which I thought was very interesting. So this was by Frederica [inaudible 00:28:45], I think that’s how you pronounce her name, on behalf of her graduate student, Alice Rodney. So, in their group, they studied the reciprocal interaction between alpha-synuclein and the lysosomal homeostasis, and they did this in iPS-derived synucleinopathy models. So, they demonstrated that in cells that had mutation in the gene that encodes alpha-synuclein, which is SNCA. This was a triplication of the gene, but the endolysosomal trafficking system was impaired, so the proteins that need to be expressed in the lysosome can’t get there. Specifically, they demonstrated that the transport of immature lysosomal cathepsins proteins is disrupted. So this then reduced the levels of mature of cathepsins and the lysosome, and I’m biased because cathepsins are part of my PhD program. So I was very excited. I was taking lots of notes.

Anna Wernick:

But what’s really important here is that the cathepsins play key roles in the degradation of alpha-synuclein, so then this creates a vicious cycle, whether it’s less cathepsins to degrade of alpha-synuclein and then this inhibits further the cathepsins that can make it to the lysosome. But what was really interesting was that they demonstrated that when they treated these neurons with a inhibitor, a farnesyl cell transferase inhibitor, which is currently used in cancer treatments, this was able to rescue like lysosomal farnesyl expression in SNC and mutant mice. This was in vivo. They demonstrated that this could then, I guess, be a potential therapeutic target in PD, and what’s good is that this is already a drug that’s demonstrated to be safe in human patients. So I thought that was quite interesting.

Anna Wernick:

Another talk that I thought was really interesting was Don Cleveland’s talk. He’s from the University of San Diego and he gave this talk this morning. In his talk, in his lab, they’ve been using antisense oligonucleotide or ASOs. That specifically inhibit or suppress the expression of PTB1, which is expressed in radial glial cells. This basically converted the idea entity of these cells into neurons. He’s shown that this can actually… Even though this is only transient suppression, these neurons managed to survive. And months later, they’ve extended dendrites and axons and they found about 8% more neurons in these mouse brains that they were before. He demonstrated later in his talk that this could be a potential therapy for Parkinson’s disease. So they had a toxin model of Parkinson’s disease called the 6-OHDA mouse model, and they demonstrated that they could actually reverse the lesion in these lesioned mice. Most of the mice got better within a three-month period after receiving this ASO treatment as this converted the glia into nigral neurons, you guys.

Katy Hole:

You explained it pretty well. Amanda, do you have any comments on that? It’s quite cool, isn’t it?

Dr Amanda Heslegrave:

I mean, yeah, that sounds quite amazing to me. I didn’t go to that talk, and I’m sorry I didn’t, but-

Anna Wernick:

It was really cool.

Dr Amanda Heslegrave:

… as I said before, you can’t be in all of them all of the time.

Anna Wernick:

No, there’s so much going on.

Dr Amanda Heslegrave:

Yeah.

Katy Hole:

Yeah. What about you, Percy? I saw you nodding along at the beginning.

Dr Percy Griffin:

No, I think it’s very interesting technology, ASOs, because I think they’ve been applied in other disease areas as well, so it’s interesting seeing it in our space. But also the fact that you’re able to change a glial cell to a neuron, that’s really cool. I guess I was going to ask this, but it sounds like he didn’t look at stem cells necessarily and potentially inducing neurogenesis with that, because I think about what would happen if they lost the glial cells that they needed for particular parts of the network of the brain. So, that was what I was nodding on about and being very excited about quietly in my corner.

Katy Hole:

Cool. Anna, do you have anything else?

Anna Wernick:

No, I was just going to say that, yeah, he didn’t mention anything about stem cells. I imagine it would purely be because it would be a bit more complicated to induce conversion into what cell type, because I think it was amazing to me that you could suppress one gene and that it would completely change identity. I guess they only looked at the radial glial for that simplicity. But yeah, I did think that too, like what are these glial cells doing. Are they serving a function that is important, but I guess because they’ve seen these behavioral changes that are positive that he didn’t report any negative effects in his talk.

Katy Hole:

Yeah. Well, we’ll wait for the paper and see if that’s in the small print. Okay. So, we’ve not got much time left, so I’ll just finish with a couple of points. So, last week’s podcast featured Henrik Zetterberg and he’s been very present this week, chairing, hosting and presenting. I wonder, maybe Amanda or Wager, how much of the progress we you’ve been talking about is down to him? Yeah. Would you like to comment on that?

Dr Amanda Heslegrave:

If there’s anyone in the scientific world who can get people together and collaborate and give the enthusiasm that it needs for that collaboration to happen, then it’s Henrik. So, I’m guessing that he is at the center of all of it. Do you think, Wager?

Wager Brum:

Yeah. Yeah. I think so too. It has been a wonderful experience to be there in Gothenburg working with him and Kai. I mean, it is just walking around the conference and you see Henrik is always with everyone and he’s always like… You know that he’s not just saying hello to the person. He’s probably starting a collaboration or maintaining a collaboration, and I think it’s really important that… We need scientists like that, that collaborate with people around the world to make it such a nice team effort.

Katy Hole:

Yeah, he sounds like the best kind of person and just what we need in the world right now, don’t we?

Wager Brum:

Yeah.

Katy Hole:

So, that’s great. So just one last thing, on Tuesday, we had the pleasure of hearing from Nobel laureate, Thomas Sϋdhof, discussing regulation of synaptic function in Alzheimer’s genes. I think, Percy, you went to that talk. Would you like to comment?

Dr Percy Griffin:

I was at that talk, and it was, again, very fascinating to see because it’s very much in line with what I talked about from all Oleg Butovsky’s talk as well, is that we have this one view of know these particular proteins are bad, these particular proteins are good. He was talking about how APOE can induce MAP-kinase signaling, and that leads to further APP transcription and that changes endlysosomal size and forms synapsis. But the canonical view of APOE is that it’s bad for of the brain and the leads to Alzheimer’s disease. So, what does this mean?

Dr Percy Griffin:

In his talk, he went through the signaling cascade and he was very, very open about the fact that this was in a cell culture model and this was work that is very preliminary. But at the end of the talk, he ended almost perfectly by saying, “I’m not going to give you any conclusions because I don’t know,” and that’s okay for a scientist to say too, like we don’t know. We have more questions that we want to answer. And that’s what I like about this conference and being around people again is that there are more questions. There are no conclusions. There’s still Alzheimer’s raging out there. There’s all of these other dementias. We have questions on how to diagnose it, how to treat it and how to reduce the risk of the disease. So, more questions is good as well, and that’s the biggest thing that I took away from this fantastic plenary.

Katy Hole:

Yeah. I think Bart De Strooper did the same. It’s literally the definition of science, isn’t it? We don’t know, and that’s why we’re looking. I don’t think we’ll ever get all the conclusions. So, we’ll keep going with that.

Katy Hole:

So, I know we’re all keen to get back to the conference, and Anna has already ditched because she had one GBA meeting. It was now. So, that’s probably all we have time for today. I would like to thank our awesome guests, Wager Brum, Amanda Heslegrave, Percy Griffin, and Anna Wernick.

Dr Amanda Heslegrave:

Thank you.

Dr Percy Griffin:

Thanks. [crosstalk 00:36:49].

Katy Hole:

It was really nice to meet you. We have profiles on all of today’s panelists on the website, including details of their Twitter accounts, so please do check those out. Finally, please remember to like, subscribe and leave a review of this podcast through our website and in your favorite podcast app. It would also be great if you want to comment and share your own highlights. I’m Katy Hole. I’ve been your host for today, and I look forward to joining you again. Thank you. Adios.

Dr Amanda Heslegrave:

Yay.

Wager Brum:

Yay.

Dr Amanda Heslegrave:

Good.

Voice Over:

Brought to you by dementiaresearcher.nihr.ac.uk, in association with Alzheimer’s Research UK and Alzheimer’s Society, supporting early-career dementia researchers across the world.

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