Podcast – Decoding Familial British Dementia

Voice Over:

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

Dr Aitana Sogorb Esteve:

Welcome to the Dementia Researcher Podcast. Today's episode focuses on familial British dementia. We'll be discussing the latest research findings from stem cell models that are helping to shed light on the disease mechanics. We'll also hear about the Race Against Dementia Ignition Fund, which has made a massive difference in making this and my own research possible.

I'm Dr. Aitana Sogorb Esteve, a Race Against Dementia Alzheimer research fellow at University College London, and I'm delighted to be hosting this show. Joining me today we have Dr. Charlie Arber and Sam Crawford from the University College London. Charlie is leading the development of human stem cell models to study neurodegenerative diseases and Sam, a PhD student, has been working closely with Charlie on understanding familial British dementia. Hello both of you and thanks for joining me today.

Dr Charlie Arber:

Thank you for having us.

Sam Crawford:

Hi. Yeah, thanks for having us on.

Dr Aitana Sogorb Esteve:

Well, so I said your names hopefully right pronunciation. I'm sorry about that. But why don't you all introduce yourself? I think you'll do it better than me.

Dr Charlie Arber:

My name's Charlie Arber. I've been at UCL for a little while now. I'm a senior research fellow. Yeah, as you said, I use stem cells to try and understand some of the earliest events in dementia, recently focusing on inflammation and amyloid. Today you'll hear a bit more about familial British dementia, which started as a bit of a side project, but we've got really excited about.

Sam Crawford:

Hi, I'm Sam Crawford. I'm just coming to you. End of my first year of my PhD. I joined UCL in 2022 as a research technician, and I was shared between the Institute of Neurology and the Dementia Research Institute setting up stem cell experiments between lots of different groups, which was really cool. And then I was very fortunate to be awarded an ARUK scholarship for my PhD studies, which started October last year. So, like I say, just coming to the end of my first year now. We're going to talk a lot about familial British dementia, which is really exciting, and that is very much the centrepiece of my PhD project. So, thanks to Charlie for getting me involved in this and I hope we can sort of convey some of our excitement over the next few minutes.

Dr Aitana Sogorb Esteve:

Great, thank you. Well, congratulations you both on the funding for PhD and for continuing the research. Well, let's learn all about it from our experts. Well, let's start by setting the scene for our listeners. Well, you are the expert here, so could you give us an overview on familial British dementia, because actually I haven't heard about it before until about a year ago that I started hearing about it from you, Charlie. So, what is it? How is it caused? What makes it different from other dementias like Alzheimer's disease, for example?

Dr Charlie Arber:

I'll give a quick overview of some of the clinical background. It's also a disease that I'd never heard of until working with some of the cell’s thanks to Selena Ray who runs the lab here and some of the pathologists in the Brain Bank downstairs who are really world leaders in it, like Tammaryn Lashley.

Familial British dementia was first described in 1933, and it's super rare. It's nothing to do with Brexit. There is no British dementia jokes inserted here. But it's basically affecting one family, one very large kindred now. So, we think around five or six people in the UK who might be affected and maybe a few dozen worldwide. It first affects people around the age of 50 and they have a progressive dementia, so very cognitive led, a bit like other dementias that we know about like Alzheimer's disease. But there are also some movement disorders, so there's a cerebellar ataxia component and also spastic paraparesis. So, you can see some differences with familial Alzheimer's disease, for example. But yeah, as I mentioned, we work very closely with the pathologists in Brain Bank. Sam, a little bit about the pathology, don't you?

Sam Crawford:

Yeah, the pathology is really interesting, actually. It has some interesting parallels and some important differences with Alzheimer's disease, which is one of the most interesting facets of this. Notably, you have a lot of amyloid pathology and a lot of cerebral amyloid angiopathy as well. That is plaques that are associated with the vasculature in the brain, and specifically the amyloid plaques that we see are restricted more to the limbic system. So, in Alzheimer's disease, you see a widespread plaque load across the neocortex. We don't see that quite as much in familial British dementia. We see it more restricted to the limbic system, so we have quite severe hippocampal pathology, for example. We also have tau pathology as well, and again, that is more restricted to limbic areas. Actually, the tau is exactly in the exact same conformation as we see in Alzheimer's disease, which is super interesting.

The key difference with AD is that the protein which forms the amyloid is not A beta as we see in Alzheimer's disease, we call it ABri, and we'll talk about that in a little bit. But in terms of the actual structure and how the plaques appear under a microscopic histologist, they look not really different to how A beta looks.

Dr Aitana Sogorb Esteve:

Very interesting. Well, I've read your publication, which is available in bioRxiv, and you talk about not only the British dementia but other local dementias. So, are they just named differently depending on the family they are from, or they have different aspects of it?

Sam Crawford:

That's something that's super exciting as well, is that in recent years we've had an expansion of the number of families which have had an ITM2B, which is the gene implicated in familial British dementia, that have had a mutation that we assume to cause the dementia. In 2021 we found out there was a Chinese family, so they called it familial Chinese dementia, and then in 2023, a Korean family. And both of these families have a fairly similar mutation as what we see in familial British dementia. However, much earlier on there was a Danish family identified with a mutation in a similar area. Mutation is slightly different, and again, I'll talk about that in just a moment. But essentially these families have sort of been grouped together since the mutations are proximal to each other and the dementias are assumed to be the same. We don't yet have pathology for the Chinese or Korean families since they were only identified in the last three years or so, but that's probably something that will hopefully come in due course.

Dr Aitana Sogorb Esteve:

Very interesting. So, then kind of staying with the genetics of this ITM2B gene, probably Sam, could you explain how this mutation leads to the production of this ABri amyloid type, and it results in this formation of the plaques?

Sam Crawford:

Like you said, this is a mutation in a gene called ITM2B. It was previously called BRI2, so some people might have heard of it in another context under that name. We don't fully understand, as is often the case, the function of this gene and the protein at this stage. There have been some putative functions and people have noted that perhaps it has some interaction with APP and APP processing and things like that, and it also has this conserved domain, which has apparently some chaperone functions with areas of other proteins that are prone to amyloidogenesis.

But specifically with the mutation in familial British dementia, it disrupts the stop codon at the end of the gene. And what's interesting is that causes an extension of the C-terminus by 11 amino acids. And when the C-terminus is cleaved by a protein called furin, that results in an extended peptide. So ordinarily in the wild-type conditions in patients which aren't mutation carriers, we see the release of a C-terminal fragment called BRI23, which is just 23 amino acids. However, in familial British dementia, that is extended to 34 amino acids, and we call that ABri. And that is the protein that aggregates in the brain and forms those plaques.

Dr Charlie Arber:

We think that's super exciting that we have this different peptide forming these amyloid plaques, it's not A beta, it's ABri, but yet the downstream changes are similar. Changes in tau, neurodegeneration, and dementia. So, it's almost like an alternate amyloid cascade starting with a different protein.

Dr Aitana Sogorb Esteve:

Sorry. Yeah, it just complicates more the picture as it is right now, right? So then, Charlie, what about tau? What is tau? Is it similar pathology as in not a primary tauopathy, but what does it do? How does it compare, the tau pathology in British familial dementia and Alzheimer's disease?

Dr Charlie Arber:

I think, as Sam mentioned, tau seems to follow the amyloid pathology quite a lot in areas of the brain. So, the pathology is quite strong in the limbic regions, for example. But I think what's written is that anywhere where you see this amyloid build-up, you see changes in tau. What's really interesting is work recently. The cryo-EM-type studies have looked at the tau fold in familial British dementia, and it looks almost identical to the Alzheimer's disease fold and some of these secondary tauopathies, which really links some of the disease processes, I think. So, the primary tauopathies look a bit different, whereas the secondary tauopathies like Alzheimer's disease, even Down syndrome now, and familial British dementia, the tau pathology looks similar. So, it seems to be a downstream event leading into this possible alternate amyloid cascade.

Dr Aitana Sogorb Esteve:

I think the three of us, we are fundamental scientists and very focused on the wet lab and the molecular bits of it, but maybe just moving aside from that for a moment. Could you tell me which are the common clinical manifestations of familial British dementia? Is the progression with time and is there a way that we can now diagnose it? Any biomarkers that are specific of it?

Dr Charlie Arber:

I think what's so important to note is how rare this disease is, so few people come to the clinic with it. I think the biggest factor is a family history. I think this is a dominantly inherited mutation, and I think it runs in this family, the single big kindred. In terms of biomarkers, I think, again, it's so rare that people haven't looked yet. We can predict what it would look like, and I guess there'd be similar changes to some of the other dementias, neurofilament light might track with neurodegeneration and we might see changes in tau similar to other dementias.

But I think in terms of the clinical progression, it's quite anecdotal. But what's really interesting is that when these people start to develop symptoms in their late forties, fifties, it seems to be associated with head trauma or some kind of infection. One person had the flu, one person had another sort of head trauma, and then there's some kind of progression from that. So that sort of links into what we'll be talking about soon in confirmation and the onset in British dementia without trying to steal our own thunder.

Dr Aitana Sogorb Esteve:

Yeah, we have a hint there of what's going on. Cool. Well, it's very interesting. I think it will be super cool to see if we can measure ABri in fluids. So that will be really, really interesting.

Sam Crawford:

Yeah, I think that's something that's quite exciting because we know that ITM2B is expressed in peripheral tissue as well, so there's no reason why we shouldn't be able to detect it also in tissue. And the pathologists have told us that they see the pathology, as I said, in the tissue as well. So, there's no reason why we shouldn't be able to measure it elsewhere without being so invasive. It's going into the brain. But obviously as Charlie mentioned before, the lack of patients, since it's super, super rare, makes it quite difficult to get the sheer numbers you require to do something really powerful in terms of biomarkers. But it certainly, as Charlie mentioned, would be really cool to look at NFL and things like that.

Dr Aitana Sogorb Esteve:

Now that we are kind of very well-known on familial British dementia, we know everything about it, I'd like to focus on the science on stem cells because I find it very cool work, honestly, and it takes a lot of time, so I really admire you guys working on stem cells. I've been there and I know how much time it takes. Well, Sam, your role focuses on using stem cell models to study dementia. Could you explain how you use these induced pluripotent stem cells to model familial British dementia in the lab?

Sam Crawford:

Yeah, we are really fortunate in Selena Ray's lab here. We have some very close connections with clinicians at UCL and also the Biobank. So, we have really exclusive and fortunate access to patient fibroblasts. Specifically, we're interested in skin biopsies that are taken from patients with genetic forms of dementia. In this case, it's familial British dementia. In times one by Charlie's used patients with familial Alzheimer's disease to produce some really amazing work.

What we do is we take those fibroblasts from the skin cells, and we expand them in culture, and then we can use the Yamanaka factors, which are packaged into these vectors which we transfect into the cells. And then over the course of 20 or 30 days, we can reprogram them into stem cells, which we then expand and bank, and then we can use them to perform differentiations into a cell type of interest. So theoretically, they could become any cell type. Specifically, we're looking at neurons, microglia, and astrocytes in the lab, so we have lots of well-defined protocols now to generate these types of cells so we can sort of try and, fairly simplistically, but very effectively, model brain cells in a dish which have the exact same genetic background as the patient from which they came. And this is sort of the crux of a lot of the work that goes on in Selena's lab. Charlie and others have a lot of expertise in this area, and it allows us to perform some really cool experiments. We'll discuss in just a moment about how we've applied that to this project in particular.

Dr Aitana Sogorb Esteve:

Yeah. I think, Sam, you covered part of it, but Charlie, what do you think are the benefits of using stem cell models for studying dementia in general, but these kinds of rare types of dementia may be related to the rarity of it, right?

Dr Charlie Arber:

I guess there are lots of different ways to study dementia and every type of model comes with advantages and disadvantages. But until the last, I guess, decade, the one thing missing is the chance to study live human brain cells in a dish. And that's really, as Sam said, one of the use for using stem cells are really opportunities. I think for this project in particular, as Sam mentioned, we can turn our stem cells from these donors, from these people into neurons, astrocytes, and microglia, and then really try to understand the contribution for the different cell types to the disease mechanisms and what's going on really early in disease. And I think that is really one of the powers that's coming out in this project, is the ability to study the different cell types in isolation rather than in the late-stage disease context.

Maybe I can talk a little bit more about some of the early phases of the project. Obviously, we're studying a dementia here, so the first thing we did was really focusing on the neurons. We had Emma who was a master's student, and she was working really hard trying to understand the role of ITM2B, this gene, in neurons and trying to understand whether she could see the amyloid. We did so many experiments, we were banging our head against the wall, and finally we realised maybe this isn't a neuronal gene, maybe the expression is higher in microglia, which is supported by lots of these online tools that we were looking at.

We started to turn our stem cells into microglia rather neurons, and for the first time, we could see lots of this gene being expressed in the microglia. And then when we looked in our patient cells, which have this extension to the gene which produced this amyloid, which isn't produced in healthy control microglia, for the first time, we could start to detect this amyloid-free protein, this amyloidogenic peptide in our patient microglia and not the neurons. This really suggests to us that amyloid is coming from the microglia and not the neurons, which was a totally surprising finding and not at all what we were expecting. But poor Emma spent months banging her head against the wall in the neurons until we worked out that it was in the microglia, and we needed to start again in a different cell type.

Dr Aitana Sogorb Esteve:

Well, that explains the symptom onset as well that you were saying before. Okay, I'm going to pause here on the science bit and just ask you guys, how does it feel to find out that super unexpected results, that you've been kind of doing experiments, "This doesn't work, this doesn't work." Suddenly, "Wow, big discovery." How does it feel?

Dr Charlie Arber:

I guess the first feeling was, "Oh, that's unexpected and a bit surprising. Maybe we should just write this up as a small paper." We didn't really understand the significance straight away. Well, I didn't, in my head, anyway. I was like, "Oh, that's a bit weird." But the more we thought about it, the more excited we got about it, that potentially this amyloid isn't coming from neurons, it's coming from microglia. And the more we thought about it, I guess the more excited we got and spoke to more people. They were like, "Hey, this is a really big finding." We're like, "Oh, yeah. It is." So, I think we've been increasingly excited about it and the opportunities we've got from that observation are still growing now and it's quite exciting to work with.

Sam Crawford:

I think it's especially cool in the context of the pathology of the disease and the presentation of the patient. We alluded earlier to the similarities between patients with FBD and with AD in terms of their pathology. And I think the fact that you have what we believe to be an amyloid, which is derived from a different source of cells, so microglia, causing dementia and with similar spread of amyloid and then tau pathology, I think that asks a lot of important questions. I think that's something we're trying to tease out slowly over the course of the next few years. But I think that's really exciting for our understanding of Alzheimer's disease also. So yeah, pretty cool.

Dr Charlie Arber:

I don't know if you're the same. When you've got a finding that you're not expecting, you're always doubting yourself as a scientist. But really excitingly, another lab, [inaudible 00:19:53] lab in New York, had a similar finding, which was uploaded to bioRxiv I think the same month as our preprint showing the same thing in mouse models. It gives you a lot of confidence that you're not making it up. So that's always good to see.

Dr Aitana Sogorb Esteve:

That's great. Yes. What about other cell types? Have you seen anything in astrocytes, for example?

Dr Charlie Arber:

I think the first thing to say is that this gene, ITM2B, as well as being highly expressed in the microglia in the brain, macrophages throughout the body express high levels of it too. And this, we think, explains why there are papers from pathologists two decades ago showing that you can see amyloid buildup in every organ of the body throughout the body. You can see it in the skin, you can see it in the eyes. And I think anywhere where you'd see a tissue resident macrophage, maybe that's explaining why you start to see this pathology.

We do see it highly enriched in the microglia in our cultures. That doesn't mean that it's only expressed there. I think there are papers suggesting in certain astrocyte responses there can be expression of ITM2B. So, I guess akin to APOE where you can have different cell contexts, and you can have different expression in astrocytes and microglia. That's work that needs to be teased out in the future. But under basal conditions, ITM2B is one of the most highly expressed genes at microglia, so that's why we're following the work down that route.

Dr Aitana Sogorb Esteve:

That's very interesting as well, because I think we might need to maybe change a little bit our focus. I was in this conference last week, I came back on Sunday, but actually they also saw a TDP-43 aggregate in the skin cells. So that will be very interesting to see also that, yeah, maybe we are not looking at everything we have to look at.

Dr Charlie Arber:

And a great opportunity for biomarkers as well, rather than having to go in the brain.

Dr Aitana Sogorb Esteve:

Yeah, definitely. Yes. You guys measured the actual ABri. How do you isolate it, as in the protein, from the cells and measure it in the lab?

Sam Crawford:

Our main method of detection is by Western blot. What we generally do is we generate our microglia or neuronal models or astrocyte models from the iPSCs that we mentioned earlier. We grow them for different amounts of time depending on the specific question we're trying to answer. For neurons that might be approximately a hundred days, but for microglia, they can be produced from 20 onwards to towards 80 days. We grow them in the lab as monocultures at the moment, and then we'll take media and cell pellets and then we can extract protein from those sources and then measure them using antibodies via Western blot. And like I said, that's how Charlie and Emma and co stumbled across the fact that the microglia were the ones that were producing it in the first place.

Specifically, we're interested in the media because as I mentioned earlier, this protein is cleaved and it's cleaved out of the cell. So, when the cells produce it, they leach out into the media, which there it can be detected, and then we can try and quantify that and understand how production of ABri in this instance might go up or down in a given context.

Dr Aitana Sogorb Esteve:

And then maybe, Charlie, this is a question for you, do you think that similarities between familial British Alzheimer disease, that new therapies should be maybe focusing on targeting microglia or therapies targeting microglia could be effective as well in the future?

Dr Charlie Arber:

I think it's a really important opportunity that we have now because we've got this different amyloid cascade starting potentially with the innate immune system, and trying to understand the role of microglia and innate immunity in the earliest phases of disease is something that a lot of people are working on in Alzheimer's disease. But the fact we've got this single cell type making an amyloid that we can manipulate the immunogenic environment, we can really have a platform to then understand the interaction between inflammation and amyloid. And I think the similarities with Alzheimer's disease are that you have an amyloid and you have downstream tau as the cascade as we picture it at the moment. The fact that we can disentangle the amyloid and inflammation in one cell type in British dementia means that we have a platform to study how that can influence neuronal tau now. And I think that's a really exciting opportunity we have from this platform.

For example, can you disentangle, can you stop that interaction going from an amyloid phase to a tau phase? We know that that's possible thanks to some really rare mutations like the Reelin-COLBOS in Colombia and the Christchurch mutation where you have mutations that destine you to develop Alzheimer's disease, but yet the onset is three decades, four decades later. So, people can escape their genetics, and so that shows that there is a possibility to disentangle the amyloid and tau phases of disease. And I think we've got a good platform to then study that a bit further.

Dr Aitana Sogorb Esteve:

Wow, that's very cool. I think I'm going to come back here a little bit to the similarities in pathology. Because in Alzheimer's disease we see a lot of co-pathology, there are a lot of cases that also have TDP-43. Have you seen in your models ABri in Alzheimer's disease patient cells?

Dr Charlie Arber:

The ABri peptide itself is only made because the stop codon is disrupted by the mutation of amyloid.

Dr Aitana Sogorb Esteve:

I see.

Dr Charlie Arber:

However, the gene itself, ITM2B, we think has a normal role in response to inflammation. Our work together with Dervis Salih in the Dementia Research Institute suggests that this gene ITM2B is hugely upregulated in the down response or the amyloid-responsive microglia. Actually, papers are still coming out now. One was highlighted last week where ITM2B seems to be upregulated in Alzheimer's disease. So, you might not be seeing ABri, but the normal function of the same gene is in response to amyloid and disease, so maybe in these people with British dementia, that response leads to the production of more amyloids and potentially a worsening of disease onset. So, it's like the microglia trying to mount a protective response, but actually in reality are making more of this amyloid protein and are worsening the disease as it were. So yeah, I think there's lots of opportunities to study ITM2B and other dementias. However, the tools aren't great, and the antibodies need some work.

Dr Aitana Sogorb Esteve:

You have already found some amazing things, but I guess there are still a lot of questions that need to be answered. So, looking ahead, what are the key next steps in understanding the role of microglia in familial British dementia?

Sam Crawford:

We spoke about its kind of briefly earlier, but our ability to generate microglia and neurons separately is really cool because we can look at them in isolation from each other and try and understand what their function is, like I say, in a monoculture. But also, we can start to look at things like co-cultures, so combining both microglia and neurons and try and understand, "Okay, if we believe that the amyloid peptide is coming from the microglia, how does that or does that affect neuronal health in our cultures as we predict that it perhaps does in the brain?" And that's what causes the neurodegeneration. And so, it'll be interesting for us to try and use the genotypes of the cells that we have in order to try and assess the true impact of that.

So, can we combine disease cells, for example, diseased microglia with healthy neurons, and does that have an impact on them in our cultures? And through various measurements, we can try and understand how neuronal function is impaired and perhaps do we see any neurodegeneration. That might be a bit of a push at this stage. Like I say, we're still very much in the early stages of this, but we have a very powerful tool in our stem cells in order to try and, like we said earlier, just tease out the exact mechanisms that are at play here and try and understand if this has wider applications to other disease processes.

Dr Aitana Sogorb Esteve:

Charlie, do you have anything to add? Next steps of it?

Dr Charlie Arber:

Yeah, I think Sam's summed it up really well, but as well as that we have now these tools from these people with this really rare dementia, meaning that maybe we're in a position now that we can think about the first therapies for these people. As well as rolling it out to dementia more widely, maybe, first of all, we should focus on this really rare monogenic disease, and that's also work that we're hoping to start soon. So, can we make a difference to these people as well as the understanding of the disease mechanisms?

Dr Aitana Sogorb Esteve:

Well, now we know more about familial British dementia, stem cells, microglia, so I think it's time to talk about funding. Well, as I mentioned at the start of the show, Race Against Dementia have not only funded my own fellowship, but last year they launched the first Ignition Fund programme which has also funded another of my projects likely, but also has helped you, Charlie, with the funding. I think I'm going to ask you if you can explain what this Race against Dementia Ignition Fund is about and why it was established.

Dr Charlie Arber:

I think you might be better to comment on this than me, but the first thing I'll say is the real ethos of Race Against Dementia is to bring some Formula 1 mindset to the dementia research field. So really accelerating dementia research and taking some of the mindset from Formula 1 and translating that across to dementia research. Specifically, the Ignition Award I think was set up to really exploit some surprising and unusual findings that might otherwise be harder to pursue. And I think the idea was to really take surprising findings that might go against the grain, might be a bit different from what other people are working on just in case that's exactly what we should be working on and trying to exploit some of those findings for maximising the outputs and opportunities. Did I sum up Race Against Dementia okay?

Dr Aitana Sogorb Esteve:

Yes. Yeah, yeah. Perfectly. Yes. Yeah, I think that was definitely the goal of it. That then all this kind of extra money on funding that you have for Formula 1 to kind think out of the box, do something different. Sometimes when you are kind of linked to a project, you might not have that kind of space or money to do that, so I think they're really promoting this. So how was the funding from this Ignition Fund help accelerate your work on familial British dementia? What is it in it for you?

Dr Charlie Arber:

I think it's a really unusual call because I think it's research funding up to £100,000, which can go towards equipment or headcount or research costs. And so, the fact I think they're aiming it more towards early-career researchers means that that really allows you to hire a technician or to follow up on these unexpected findings, which might otherwise not be possible. And there aren't many calls out there which are similar. So that's really helped us to expand our capacity in this project. So, we've hired Lucrezia, an amazing technician who's just started and starting to address some of these questions that we were talking about just now. And I think some of training as well. We had a Race Against Dementia Day last week, and some of the things that might make a difference in a Formula 1 world, some of that training is going to really help us as a team and maximise some of these surprising findings.

Dr Aitana Sogorb Esteve:

Yes, indeed. Well, I think it's also very good that it's so flexible that you can diversify the money that you get on hiring people, which I think at our stage is quite important. For me, it was the same. With the Ignition Fund, I managed to hire my first research assistant, and that makes a huge difference on the project and the research that we do. Yeah.

Well, we saw each other at the Dementia Forum Day last week, and I think you just started, probably, but what do you think which expectations you have in terms of collaboration with other Race Against Dementia Fellows? Because now they also have the teams funded with support from the Rosetrees Trust as well. So, we are quite a lot now in the Race Against Dementia family. I already have a project together with one of the other fellows, [inaudible 00:34:00] in Cardiff. So, I think they're really kind of interested in collaboration, cross collaboration. So how do you see that?

Dr Charlie Arber:

I think there are lots of opportunities, and just as one example, one of Sam's collaborators for his PhD project was there at the Race Against Dementia Day last week. So that's York who's going to be working with Sam a bit. But in terms of the project going forward as well, I think there are so many opportunities working with yourself and studying tau in these cultures, as well as some of the Race Against Dementia fellows that we know already. There are so many opportunities and it's about coming together and discussing that, which sometimes isn't always possible. So, I think what I really enjoyed is just discussing it more and then trying to make those collaborations happen. But I'll be bothering you in the next few weeks, Aitana.

Dr Aitana Sogorb Esteve:

That's completely fine. I'm really interested on your project, guys. Well, there will be some people listening who have applied to the current round, but I think they just extended it until yesterday. Yeah, I think they extended the call until yesterday. But do you have any pieces of advice for those shortlisted this time who might apply next time or any advice about it?

Dr Charlie Arber:

I think the application process is super short and really straightforward, which I think was brilliant when time is always limited in our lives. I think try to really explain why the finding is so surprising and why that opens up new opportunities which otherwise might not be possible. And I think, yeah, just apply. I think it's a great fund and lots of opportunities. Do you have any advice for applicants, Aitana?

Dr Aitana Sogorb Esteve:

No. Yeah, I think you got it right. Just make a stress on why is this different from your current research, what is in good for that? And I think also why the mindset of Formula 1 will be really useful for our research, which is you never think about it until you arrive to Race Against Dementia, but it has so many things that we can apply and that really, really are very useful on a day-to-day basis. So yes, think about it.

Dr Charlie Arber:

Some of this funding is so important and obviously Sam is funded by ARUK as well for his PhD scholarship. I think without some of this amazing funding, this work wouldn't be happening, so it's really exciting time and space to work on familial British dementia.

Dr Aitana Sogorb Esteve:

We've been talking about Race Against Dementia for a bit now, but I have two final questions to finish up. The first one is, what message would you like to share with the public about the importance of research into rare forms of dementia, like familial British dementia?

Sam Crawford:

Firstly, I think all you need to do is meet someone who is either a family member or themselves suffering from a rare form of dementia to understand just how important the work that you do is and how important it is for everyone to really pay attention to these kinds of diseases. The generosity of the families and the patients themselves is quite remarkable. This is the case across even more prevalent forms of dementia as well. But it is really touching when you communicate with families and understand just how much it means to them. So that's on one point.

And then also, actually, unsurprisingly, John Shock can articulate this far better than I can, but he wrote a really nice editorial in one of the BMJ journals a couple of years ago where he said that the study of rare disease isn't just stamp collecting, and by that he just means it's not just something we do as a collector's item, we do it for fun because we think that we can find something interesting and then move on. But actually, in the context of neurodegeneration more generally, the study of rare disease is so, so important. And he uses the example of TREM2. So, identifying mutations in TREM2 that cause Nasu-Hakola disease has sort of inadvertently led to an increased understanding of microglial risk alleles in Alzheimer's. And I think the discovery of TREM2 mutations has sort of really rapidly progressed in the past few years our understanding of microglial contribution to Alzheimer's. Not to say that ITM2B is necessarily the next TREM2. I would love it if that was the case, that would be really exciting.

But suffice to say, the importance of looking at rare or peculiar cases of dementia can't really be underestimated because the impacts that it can have for not just the families directly involved, but also people that are suffering from neurodegenerative diseases more generally, I don't think it can quite be measured. So just to really hammer home how important it is that people consider these things.

Dr Aitana Sogorb Esteve:

Great. Yeah. Charlie, do you want to add anything? I think it was a very good answer.

Dr Charlie Arber:

Yeah, I think Sam just reminds us why we do the work for the people that we can make a difference for, and that's the people with rare disease, and then rolling out that understanding potentially in the future.

Dr Aitana Sogorb Esteve:

Well, and then the other question is, how can listeners support dementia research or get involved with initiatives like, for example, raise against Dementia?

Dr Charlie Arber:

Maybe I can start. I guess it depends on where you're listening from, but if you're listening in the UK, there are opportunities like Join Dementia Research and in the US there's Trial Match as well, I've heard. In Australia StepUp to Dementia Research. Yeah, I guess it's down to all of us to try and make a difference and do what we can.

Dr Aitana Sogorb Esteve:

Yeah. Well, I guess because we have to be ambassadors of Race Against Dementia as well, they have a website. Visit raiseagainstdementia.com in which there are a lot of information on how you can support the Race and the different initiatives that they do, and also the calls that they have open, because I guess there are so many researchers listening to us that are looking for that funding, so they have all the opportunities in there as well.

Well, I'm afraid that is all we have time for today. If you just can get out of this topic, this is the Dementia Researcher website where you will find a full transcript, biographies on our guests, Sam and Charlie, blogs, and much more on the topic. I would like to thank our incredible guests, Charlie, Sam, thank you so much for being here and for telling all about familial British dementia. I'm Aitana Sogorb Esteve and you've been listening to Dementia Researcher Podcast. Thank you, everyone. Bye.

Sam Crawford:

Bye.

Dr Charlie Arber:

Bye. Thank you.

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