Podcast – Changing the Course of Dementia: Four Expert Views

Announcer:

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

Emma Mead:

Hello and welcome. I'm Emma Mead. And what you're about to hear was recorded at the Alzheimer's Research UK Thames Valley Network Dementia Research Day 2026. We spent the day hearing from great speakers, sharing their research, and looking at where science is heading. And we closed with a panel on the question that the whole field keeps coming back to: What's actually going to make the biggest difference changing the course of disease? I was joined by four people who come at this from very different angles. Professor Sanjay Manohar, Professor Michele Hu, Peter Johnson, and Associate Professor Laura Winchester. Here's the conversation.

Hey, good afternoon, everybody, and I'd like to extend a warm welcome to everybody who's listening on the Dementia Researcher Podcast this afternoon. Today, we have a panel, and we are going to discuss changing the course of dementia and what will make the biggest difference. And I'm delighted to be joined here by an expert panel. And I'd like to hand over and allow our panel to introduce themselves. We'll start with Michele at the end, please.

Michele Hu:

Thank you. My name's Michele Hu. I'm a neurology consultant of nearly 20 years, over 20 years experience, and I focus on Parkinson's and atypical Parkinson's and therapies for this. But I'm also on a dual role of professor of clinical neuroscience in Oxford University, Nuffield Department.

Peter Johnson:

Hello, I'm Peter Johnson. I'm head of service for Dementia Oxfordshire. That's a service delivered by Age UK Oxfordshire. And we support everybody in the community living with the dementia diagnosis and their families across Oxfordshire.

Laura Winchester:

Hi, I'm Laura Winchester. I'm based in the Department of Psychiatry at Oxford. My interest is in bioinformatics and looking at data to understand Alzheimer's and Parkinson's.

Sanjay Manohar:

Hi, I'm Sanjay Manohar. I'm a computational neuroscientist, but I also run the Cognitive Disorders Clinic at the John Radcliffe, which sees a variety of dementia patients. So, unlike the psychiatrist who see the older age patients, we see all the younger people with dementia with Alzheimer's and slightly unusual dementias as well. And my area of interest is kind of more neuropsychiatric and cognitive features of this disease and how we explain them.

Emma Mead:

Thank you. It's great to have such a range of perspectives here on the panel today, so I think we're going to have a great discussion. So, before we look ahead, to what we think will make the biggest difference to people living with dementia, I'd like to kind of take a step back and let us think about what the current challenges are in the field. So, I'd maybe like to start with Peter, if I could, and hear from your perspective from the Dementia Oxfordshire community and think about what the people that you interact with really see as some of the biggest challenges at the moment.

Peter Johnson:

So, dealing with the dementia diagnosis is a hard and often desperate journey, both for the person with the diagnosis and their families. And probably one of the biggest challenges they face is dealing with the stigma. I mean, we've heard it alluded to earlier today that you could suffer. You get socially isolated very easily that some communities have no words for dementia. So having the conversation with your community can be very difficult and you can be inadvertently isolated and made very lonely. And I think that culturally, we inadvertently isolate and disempower the people by, for instance, if when you get a diagnosis.

For the person with the diagnosis, the message sometimes they take out of the room is my life is over. I need to prepare for the end. And for the partner, they will go into the room as their spouse and leave as the carer. They're told that they're a carer and they're expected to care for this person they've lived with as a partner for 30 years.

Emma Mead:

Yeah, I can see that that could be very distressing and difficult. I mean, Michele, is that something that you see in the clinical setting as well, or are there any other challenges that you come across?

Michele Hu:

So yes, so when you're giving somebody a diagnosis of early Parkinson's, often what people most fear is what will be my risk of developing future dementia? And also, it's increasingly a condition of ageing, both dementia and Parkinson's. So, because there are populations across the western world are globally increasing in terms of how people are living longer, we are getting really a pandemic of Alzheimer's and Parkinson's. So, one of my concerns is, are we going to have enough people to diagnose these conditions and also to effectively treat and support in the community?

Emma Mead:

Yeah, it's really important. Sanjay, maybe from your perspective, it sounds like you interact with younger people who are given sort of diagnoses. Do you see similar challenges or are there differences between sort of older populations and younger individuals?

Sanjay Manohar:

Yeah, I think the challenges are very similar. There's a massive shortage of community care for these people. And I mean, Dementia Oxfordshire did a massively important job in this where the NHS and social services can't quite stretch that far. One thing I'd say about this, this carer business is really critical. And half of the patients with Alzheimer's who we send out of the room promptly forget they've got Alzheimer's. And the other half, you know, they're very distressed by it. But in all cases, the carer is the one who bears the responsibility. There are always a proportion of people who don't have a carer and or are already kind of you know, being cared for in some way.

And they're a difficult population too. Yeah.

Emma Mead:

I mean, Peter, maybe, do you have any perspective on that where Sanjay says there are some people that don't have carers, you know? Is that something that you come across often in the Dementia Oxfordshire group?

Peter Johnson:

I think it's surprising the number of people that are living alone with dementia, either because they have no family or because their family lives a long way away, often out of county. And that can be very challenging and make it much harder to support that person.

Emma Mead:

Yeah, I can imagine that would be really difficult. And it's good that there are organisations like yourselves to provide that support and groups that can really kind of help people who might be feeling isolated and alone. So, it's wonderful to see that. I wondered maybe if we can move a bit towards that more sort of clinical perspective and think about sort of gaps and challenges in terms of how we are treating dementias and other sort of neurodegenerative conditions. And maybe, Michele, if I could come to you first, what do you see as the major challenges in the clinical space at the moment?

Michele Hu:

I think who diagnoses dementia, whether it should be, for example, a neurologist, a general physician, or a psychiatrist, is something that we haven't really coordinated very well. I personally don't think it matters as long as you actually have a good understanding and a good rapport with the patient. So, I think we need to work better with our community services in a more joined up way. So, for example, we've recently met with our community psychiatry team. Our older age psychiatrist said, and they've actually said, "We think you neurologists are better at diagnosing Parkinson's dementia, but we're better at supporting in the community. So, could you do that front aspect and initiate treatment?

And we're happy to continue it and provide community support." I think that actually is a way going forward that optimistically may make a better use of our resources and be more effective.

Emma Mead:

That's great. Thank you. And sort of thinking also about how we understand disease, and maybe I'll turn to Laura and ask, you know, what are the main challenges when we think about, you know... So, bringing together our disease understanding and combining that with our clinical practise, you know, to me, that feels like there's a bit of a gap there. I don't know if you have any thoughts about what the challenges are that we can, you know, overcome to address that question.

Laura Winchester:

So, I think there's lots of gaps there, and I think there's lots of people in the room are probably working on different bits of those gaps. I think there is a lot of work now going into not just looking at maybe cohort, but real-world data as well. So, there is people researching both. And I think it's all about what data is available and as people maybe thinking about people coming to clinics and collecting data from those people. So that's available for us to look at in addition to what we are looking at sort of collecting and designing. So, I think it's joining up those different groups and collecting as much information as possible so that we can continue to study that as well.

Emma Mead:

That sounds like a very important step. I mean is that feasible in a clinical setting? I don't know if, Sanjay, I can come to you and, you know, think about how we can tie up, you know, get collecting the right data for researchers like Laura to use it going forward to address some of these key questions.

Sanjay Manohar:

Yeah, and I think coming to a day like this, you see so much great research, and then maybe something that will surprise quite a few people is that out of, let's say the 500 patients with dementia, you know, several years with Alzheimer's disease, about 10 of them are typical Alzheimer's. The rest all have something else as well. We've heard a little bit about copathology, and you know, how you might have amyloid, how you might have Lewy body pathology, corticobasal pathology, all these other things. But also, they have vascular disease, they have epilepsy, they have head injuries, they have, you know, everything else, they have comorbidities elsewhere in their body, diabetes, and so on.

So, each patient we see has kind of a unique fingerprint profile in a very high dimensional space. And each one is unique, right? Each patient. That's the key. And when you see research that you know, ultimately, it's like labels people with having Alzheimer's or not, well, we give Alzheimer's labels on a whim, let's say. The process of diagnosing the disease is partially biological, partially social. It's partly to do with what's important and needed by that patient at the moment. And that's a bit old-fashioned, right? Because this was conceived in a day where we didn't have any disease modifying therapies.

Now if you say we're going to give treatments that target a molecule, and it becomes so much more important to get precision diagnosis to fingerprint each patient with exactly what's going on biologically. And then we've made very early steps into this by now having biomarkers that we can test promptly and quickly. Until a few years ago, until like this year, in fact, we had to get cerebral spinal fluid with a lumbar puncture on every patient if we really wanted to know the biological diagnosis, which meant that about 70% of patients we didn't bother to get the biological diagnosis, right? It's expensive, painful, and inconvenient.

But I think that is the challenge I would highlight is that everyone needs to understand the precision with which we know these labels and also think of them as inhabiting this high-dimensional space. And I think that once that challenge is addressed, we'll have much better avenues into treating this disease.

Emma Mead:

Yeah, that's so interesting. I'd like to maybe pick up at the point you made about the different sort of samples that we can gather from the clinic now, and maybe ask Laura sort of, you know, have you got some examples of how that, you know, huge amount of data now that we can gather from patients clinically can be used? You know, are there any examples from the work that you're doing for that?

Laura Winchester:

So, I think, actually, you touched on a couple of things that we're thinking about. So, looking at those datasets and pulling out... So, there is a biomarker that's working from blood now, but that's one, and maybe there are more out there. So, p-tau is looking for amyloid. We might be interested in markers for some of the other pathologies that we're thinking about. So, when you're thinking about dementia, it's a complex set of pathologies in there and we can use the datasets that we have too perhaps... Now we have the bigger datasets, you might have power to pull apart these complex problems.

So, thinking about the pathology level, but also thinking about at the clinical level and looking to see whether there's a lineup there. In some cases, there isn't, and there's a very interesting question with sort of resilience. So, whether you have a buildup of amyloid, but these patients are not showing the clinical symptoms yet. And so that group are interesting to study. And so, as we get more data on these patients, we'll be able to pull out more information about that. And it's about understanding, getting a bigger picture. And I think these datasets, as they build, become really important.

Emma Mead:

That's really interesting. Thank you. And I mean, obviously, to do these analysis, we need people to donate samples. And maybe, Peter, from your experience, you know, is there a great sort of appetite in the dementia research or the dementia community to support dementia research? And do people really know very much about how they can go about donating blood or any other sort of samples?

Peter Johnson:

I think the reality is that people with carers and people with a diagnosis are time poor. So, the difficulty is finding a way to engage with people that are overwhelmed by caring and the condition they're managing. So, I do think that they do want to engage, it's the practicalities of how you engage. And you kind of need, I mean we've talked about this previously, but you kind of need to meet them where they're at. So, if you engage with them, so we have an experts’ group that's often used to engage with people, but any of our groups that meet regularly, you'll be able to engage in a space where they feel comfortable and they'll be able to contribute. And that kind of works.

Researchers are very keen to come along and just chat to our clients. And I don't really understand how they use the information they get, but clearly, they keep coming back, so it has value. And I would say from the people that are living with a diagnosis and their carers, there's a therapeutic value of just being involved. It's giving their life meaning. That gives them a purpose. And that can make a really big difference. It's that sense of what is the point of me. It helps them retain that focus of who they are, for both the carer and the person with the diagnosis. It's a way of them contributing.

So, they are keen to engage, but often it's hard for them to do so because they're being overwhelmed by the rest of their lives.

Emma Mead:

That's really an important point. Michele, you had something.

Michele Hu:

I was saying I run the Oxford Discovery Parkinson's Cohort, which has 1,600 individuals now since 2010. And people find it really reassuring to be in an observational cohort because they're seeing often the same staff. Perhaps every year or year and a half, they're being fed back if there's anything that needs clinical care. You know, general health improved because we're measuring things like high blood pressure, et cetera, you know, as part of that assessment. And we find that people are quite willing to do procedural tests like a skin biopsy, blood tests, and lumbar puncture. And I just want to take issue. It's not painful when we do them, Sanjay.

[Group laughing] It's no more painful than when you go to the dentist and have a local anaesthetic which stings. But after that, and I've just done one about two hours ago, so we do them roughly every week for about three or four individuals and they are often very surprised at how straightforward it is. And certainly, for Parkinson's, it's becoming actually a prerequisite that you have the misfolded protein alpha-synuclein identified before you're eligible for a trial entry.

Emma Mead:

No, that's really interesting.

Sanjay Manohar:

Thank you. You're absolutely correct. [Group laughing]

Emma Mead:

Staying with clinical trials perhaps, you know, I'm interested to hear, we've obviously had quite a few clinical trials, clinical successes in the space of Alzheimer's disease in particular. And you know, we're moving to a place now where we're hoping to have more therapies in the clinic. But maybe from a clinician's perspective, how do you think we can go about improving trial designs so that we can more rapidly get the right therapies to the right patients at the right time? I don't know if, Michele, do you want to answer first?

Michele Hu:

So, one way to do it is to use a different, more adaptive trial design. And in the UK for Parkinson's, we now have the Edmund J Safra Accelerating Clinical Trials to Parkinson's or the ACT-PD. And this uses a model called MAMS, multi-arm, multi-stage. And it was adapted originally from trials that were done in prostate cancer. What's unique about this is you, for example, can have three or four different treatment trial arms going on simultaneously, which in the case of ACT-PD will be three oral medications all with different evidence for slowing down Parkinson's progression and one placebo group.

So fewer people will need the placebo, and you also have much quicker go- or no-go decisions at 6 to 12 and 18 months if you are not seeing any signal of improvement benefit within 6 to 12 months. So, I think this is now also being adopted by Michael J. Fox Foundation for their P2P or Path to Prevention trial. And I think it's going to be the way forward. We also need better ways of mitigating against things that can mess up trials. For example, placebo effect and expectation bias and learning effects.

So, if patients are really desperate that they want something to work, in fact, in the exenatide trial people, the placebo group just got better over time over the two years simply by taking part in a trial, having something to aim for, regular visits with allied health professionals and doctors, and just feeling that they were being better cared for.

Emma Mead:

That's really interesting. I mean, Peter, is that something that you've come across in sort of talking with people with lived experience?

Peter Johnson:

I would say giving people hope is a very strong therapeutic effect you absolutely see in people. It is coming back to the point I made before. It gives them purpose. They've got a reason to focus on something in a world that can otherwise feel very dark. It's not dissimilar to the importance of socialisation. It's keeping your mind active, keeping socially active. This all contributes to that and that I think that has a big effect.

Emma Mead:

That's really interesting. And I mean, thinking about the patients that we put onto these trials, obviously a really important perspective in drug discovery is that we have to have the right patients to make sure that we see a clinical effect. So, I don't know, Laura, if you've got any thoughts about that from the sort of more biomarker discovery and clinical understanding and a cohort understanding.

Laura Winchester:

Well, I was sort of thinking about this, and I guess, there is, obviously, there's an amyloid-targeted treatment. And we can now measure amyloid and we can point people to that trial or drug. And so, I guess you are thinking about now about picking out cohorts in that same way. So, making them eligible for something. I'm thinking about other therapies. Maybe when you're thinking about designing a target, you might also think about a biomarker that goes alongside it. So, if you're thinking about tau then maybe you want the tau markers.

If you're thinking about an inflammatory drug, then maybe you want to be thinking about inflammatory markers that go along to check progression or to think about end decision points as well. And so, I think there's probably parallel streams of work to be done as you think about the drug targets, what else are you thinking about in that particular cohort? So yeah, there's a lot with that understanding.

Emma Mead:

That's such an important point. I mean, do you have any thoughts about how we can create that environment to make sure we are pairing up people with that sort of expertise and understanding what the biomarkers should be and how we should go about doing them and getting the drug discovery scientists having those conversations early?

Laura Winchester:

I mean, I think just having these people. Panels like this really enable us to chat to each other. So, I myself as a data science talking to yourself as somebody from the Drug Discovery Institute, and the clinicians as well. So, it's just having joined up conversations with people who are working in this field and making sure that everybody is working towards the same thing, I think. And so, we sort of have the environment. We just have to make sure we're using it.

Emma Mead:

Yeah, it's so important. And you know, I think that that is really the only way we begin to see success, isn't it? Making sure that our data scientists, our drug discovery scientists, and our clinicians are having that good communication and obviously making sure we're involving people with lived experience to know exactly what we should be doing to inform our strategy.

Michele Hu:

I think what's really unique about ACT-PD is it's had a very active patient engagement group. And as a result, we're not doing things like asking patients to come in following overnight withdrawal of medication 'cause that's actually really distressing. People often get a lot worse, particularly if they've had PD for a number of years. Also, the main outcomes are actually not the ones that are in clinic. And there's a heavier reliance on other remote assessments that can be done at home and digital outcomes, which I think will be very important, particularly for phase three trials.

Emma Mead:

That sounds really kind of game changing actually, you know, thinking that we can have people in the comfort of their own homes still kind of reporting on the endpoints of studies. I think that that will be fantastic. I mean, again, sort of thinking about some of the clinical trials that have been ongoing and that have been in the clinic and have maybe had mixed success. And we've had some successes in the Alzheimer's field with lecanemab and donanemab, and obviously that's a little bit mixed, but I would really like first to ask maybe Peter and our clinical colleagues, you know, what the perspective of those are and then think about sort of what's next.

So, Peter, you know, what do the dementia community think about the current Alzheimer's therapies that are available to some individuals?

Peter Johnson:

No, and I think, it's quite a mix for people actually living with the condition at the moment. I mean it's hope on the horizon, but for most of them, it's very difficult for them to engage even with trials. The criteria are quite strict. And it can be challenging with the press raising everybody's hopes with these big announcements and then shooting them down with sensational follow up. And they don't know what to think and we have to be very careful about what we say. The reality is that it requires a relatively early, I'll be corrected, but it requires an early diagnosis. You've got to manage the side effects, which are exclusionary for a lot of people, et cetera.

So, we have to manage expectations and say that like you can apply for the trials, but it might actually not be good for you to engage.

Emma Mead:

Yeah. And it's so difficult to manage those expectations, isn't it? I think, in a clinical setting I mean. Sanjay, you know, in your experience, are patients excited about these sorts of developments or is it, as Peter mentioned, a bit of a mixed reception?

Sanjay Manohar:

So, with most patients who we diagnose with Alzheimer's, I would talk to 'em about these therapies, mainly because they're in the news and everyone has questions about them. But in pretty much all the cases, now, of course, it depends on what you tell them, doesn't it? But in most cases, when I give an honest description of the findings, they all come out thinking, "No, it's not ready for consumption yet," particularly when you describe, you know, the profile of the care they would need, the effects that could happen. And in particular when you tell them that the statistic that it prolongs life by four months-

Peter Johnson:

But not improving the quality of their life.

Sanjay Manohar:

And this is the thing. What patients are most afraid of when they come out clinic is being a burden. Can you imagine? This is actually what a lot of them say to you is that "The other thing I'm most terrified about is being a burden," to their partner, to society. It must be a terrible feeling to have actually. What we need to strive towards is therapies that improve the quality of life that people have, right? That's what's needed. And when a therapy is touted as prolonging life, yeah, I think they all know what that means actually.

Emma Mead:

I think you've raised a really important point there about improving quality of life. And I wonder, you know, we have so many different types of therapies now entering the clinic. There's been a bit of a focus on disease modifying and that being a bit of the sort of the thing that everybody's striving for. But actually, I wonder if symptomatic treatments might be something that patients are, you know, have more appetite for. Is that sort of your perspective there, Sanjay?

Sanjay Manohar:

That would be my intuition in talking to a lot of them. It's something that can make them feel better, even if it's short term. Exactly of as much benefit, if not more than, something that really attracts things on, which is, you know, that's how they feel about it. Of course, in reality, there will be two months of better-quality life too. And is the, you know, the amount of treatment they have worth that? That's a second question. That's a nice start question, you know? That will be addressed and will improve as well.

Emma Mead:

And Michele, what's your thoughts on that? Are your patients looking for symptomatic relief or disease modifying therapies? I mean there is scope for both, but...

Michele Hu:

Yeah, well, we're quite lucky in Parkinson's 'cause you know we have a lot more symptomatic drugs that are really quite effective. We can replace the levodopa. We can give dopamine agonists. We can use enzymes to make it hang around for longer. Then we also have things like deep brain stimulation, and we can give pump therapies. So, you know, I think, less than 5% of all of our patients with Parkinson's will be suitable for these device therapies or DBS in any case. And I would posit, probably, similar or even less will be suitable for the current disease modifying therapies that we have. I think there are also lots of other potentially more effective, low-cost pragmatic solutions.

And in Parkinson's, the evidence that regular high-intensity exercise three times a week, and a diet, a change in diet away from processed foods to more, you know, less animal-based proteins, less fried food, sort of African heritage diet, really slows down progression. But we haven't got enough data to look at it beyond 12-month duration. And that's one of the studies that I would love to do. And I don't see why that wouldn't also be the case actually in Alzheimer's or other forms of dementia.

Emma Mead:

That's really interesting, and you know, maybe something for the data scientists to collaborate with the clinicians on to try and understand that. I mean, Laura, is there anything that you are doing in that field to understand sort of prevention versus treatment? Or do you know of any research going on around that?

Laura Winchester:

So, I was immediately drawn. There's quite a lot of work done. I think there's probably quite a few diets, but I know the Mediterranean diet is one that people have been working with and there's some data there. I've been doing a little bit of work with looking at iron and looking at whether low or high iron might be of interest. But there's lots of different things that we might be able to do that might be disease modifying. And I think there's a quite a bit of work to be done with prevention that might be useful. I think Sana was sharing stuff earlier about multi-morbidities and thinking about maybe not just dementia but thinking about all the other things that might be going in parallel.

And she was using, well, UK Biobank, a very big dataset. So, there's a lot of work to be done in that area, not just with diets, but thinking about other things that might be prevention as well.

Michele Hu:

UK Biobank have used wrist-worn accelerometers and measured continuous sort of home living activity and shown that if you've got higher levels, you've got a reduced risk of future dementia.

Emma Mead:

That's great. Thank you. Peter, maybe just to sort of turn to you and ask what the dementia community are looking for in terms of treatment. Obviously, this might differ depending on whether you ask somebody with a diagnosis of dementia compared to their carer. But are patients looking for something that's going to, you know, change the course of their disease, suppress the symptoms, or as you know, we've just discussed, you know, potentially use a lifestyle intervention to slow progression?

Peter Johnson:

I mean I think it's very hard to give in a generic answer to that because there's different types of dementia and their personality overlap with that so much. They're all different. And you alluded to earlier, Sanjay, that you've got to tailor what you say to the individual. Some people want to work towards a cure. That's just what they desire. Other people are much more pragmatic, and they just might want to, "I want to lead a high-quality life for as long as I can and what can help with that?" It's very varied.

Whether there's a difference between the person with the diagnosis and the carer, I find it very hard to sort of see the answer to that because the reality is as the condition progresses, the carer becomes the advocate for the person with the diagnosis. They're speaking for them because they even know that person best and they're struggling to articulate the views themselves. So, I think separating those two things, I'm not sure I can give an answer to that.

Emma Mead:

Yeah, I can see it can be very sort of situation and patient-dependent and it's, yeah. But I can really see a place for everything that we've discussed in, you know, trying to tackle this really challenging, these challenging set of diseases and conditions. I would maybe like to sort of go out to the audience and ask if there are any questions. So, we have a few questions on Slido already, but please do keep them coming if you would like to pose any questions to our panel. So, the first question is for Sanjay, and this is, what role does genetic testing play in assessing younger dementia patients? And how does this fit with established disease paradigms?

Sanjay Manohar:

So, we would tend only to test genetically in clinic on the NHS if a patient is diagnosed under the age of 50, or if they have a first degree relative, and usually, first degree relative with early onset as well. Because it's very common to have a parent with Alzheimer's and then have a diagnosed with Alzheimer's just by chance. In terms of who wants genetic testing, seems to be about 50/50 if you ask patients whether they want to be genetically tested, but half of them don't 'cause of the implications for their family usually. And we will do the testing on clinically necessary grounds when it provides some kind of diagnostic and treatment implication.

So, for, you know, certain types of frontotemporal dementia, it's typical we would convince the patient that they need that test. We can't convince everyone, but most of them will agree to having the test. But it's not normally done. I'm talking about these kind of monogenic genes. APOE is not tested on the NHS at the moment. Again, this ties into the, you know, donanemab, lecanemab question. And at some point, it might be. But again, the difficulty is what do you tell someone. You've got a risk of getting Alzheimer's. It's increased by a certain proportion. Yeah, so at the moment, there's resource limitations as well on genetic tests.

Emma Mead:

Yeah, that's interesting. And maybe, actually, just a follow-up question to Laura. How useful and how informative do you find that kind of the data from genetic testing in driving our understanding of the mechanisms and of disease?

Laura Winchester:

Well, I think APOE is extremely important in driving a lot of different parts of disease in Alzheimer's. It's got an impact. In many of the research studies I do, I'm always correcting for APOE, so we consider it wherever we go. So yes, that test is very useful to us as data scientists. But actually, having the whole genome is extremely useful as well. So, to have a look at the other genes, we can look at genetic risk scores as well. So obviously, there are genes that we already know are associated to Alzheimer's disease, but potentially there are others out there that we haven't found yet. So, I would say that yeah, genetics is a very important study of.

Emma Mead:

Yeah, and I guess having that sort of APOE biology on the background of all of the other sort of changes that occur in the genome is vital to aid our understanding. Great, thank you. So, we have a couple of other questions. This one is directed to Michele, but also everybody. So, I'll give Michele the opportunity to answer first. What do you think causes the research gap in finding biomarkers for earlier and more precise medicine? And how can we bridge this gap from basic research?

Michele Hu:

Yeah, so that's something I've thought a lot about over the 20 years I've been doing biomarker research. I think the basic problem is we're dealing with a problem in the brain. And you know, we're not dealing with a kidney or a liver or skin problem where we can easily access diagnostic tissue, and we can use that not just for diagnosis, for stratification. And the second main problem is we have no way of direct imaging at alpha-synuclein and its deposition in pathological forms, both in the brain and in the extra central regions where we know it happens. For example, the peripheral nervous system, the gut, the skin, the heart. So those are the two key issues. So how do we start to bridge that gap?

And really there's not much. We're starting to think about this, I would say, in the last decade. So, we can measure spinal fluid, and within that, we can look at cells that have obviously come from areas of the brain as well as across the blood-brain barrier from periphery. We can then try and link that to what's happening in peripheral blood cells, PBMCs. We can look at proteomic, epigenomic signatures across both. In terms of brain imaging, we can measure dopamine deficit. That's helpful, but not that helpful.

And we can use perhaps more advanced sequences, which we're developing and others are, to look more at where the pathology is in particular the substantia nigra and the locus coeruleus and using MRI, try and directly correlate the signal change to pathological changes at post-mortem brain MRI at high resolution. So that's another kind of general approach. And then we are doing more peripheral skin biopsies and tissue biopsies to sort of start to understand more about things like the gut-brain axis, the role of the microbiome, and how inflammation might be triggered by something totally peripheral but then be recapitulated in the brain.

Emma Mead:

Yeah, no that's really interesting. And you know, going back to something you say about the sort of brain region-specific changes, something that I often kind of think about because you know, pathology doesn't happen broadly everywhere, does it? And there's a lot of heterogeneity in the way that cells respond to the pathology. So, I think that's such an inclusive point.

Michele Hu:

And lastly, I don't think we've had animal models that have particularly recapitulated either. The clinical phenotype or the pathology that we see in humans. And some of the human pre-formed fibril models of injecting alpha-synuclein into the salivary gland where it goes straight up into the brain that I've recently seen presented, I think, are very exciting.

Emma Mead:

That sounds fascinating.

Sanjay Manohar:

I was just saying that this is very exciting, but Alzheimer's disease is quite a long way behind in all of this in terms of peripheral markers. So, we don't have that gut and all these synuclein markers.

Michele Hu:

You've got amyloid and tau PET.

Sanjay Manohar:

We do. So, the thing is, amyloid and tau PET are really difficult to access. We don't have it in Oxford. We don't have it in Oxford. Where do we have it? We have to send all our patients to London for this. And the ligand's really difficult to make. So yeah, we do not have that signature yet until we had the blood markers, which obviously, looking very promising. But I think other types of marker are also looking very promising. And by that, I mean things like behavioural, cognitive, and measures that we can do in clinic, looking at how the brain is functioning. I always say to the patients that we can take pictures of your brain, but the problem with your memory is not structural necessarily.

It's to do with the way the brain is working, the computations and the neurons firing. And if the problem is at that scale, and it's certainly early in the disease, it's at that scale, right? We see atrophy in the hippocampus many years into the disease usually. So, the first biomarker is probably going to be a functional-type biomarker using behavioural and cognitive probes, I think.

Emma Mead:

Oh, that's, yeah, very, very interesting. Laura, I don't know if you want to comment about sort of finding biomarkers from a more basic research perspective or data science perspective.

Laura Winchester:

Well, I guess, I was going to conflict a little bit and say that maybe I'm still searching for the elusive fluid biomarkers, so. CSF when we have it. But also, I think the idea of finding a blood biomarker that enables a clinician to do a blood test at the GP level is really useful. And we have brilliant progression with that. Yeah, with p-tau217. I think there are trials going on where this would be moved to clinic. The question is now actually with this one is when do we use it? Because of course, you might be able to tell a patient that they have the amyloid, but what do we do next?

So, I think there is, potentially, there is that diagnostic marker with AD, but maybe we want to be thinking about other biomarkers for tracking maybe progression or back again to the drug trial. And thinking about whether we can use that to tell us more about the disease and maybe subtypes of the disease as well.

Emma Mead:

That links back nicely to what we were talking about earlier about different branches of research needing to communicate well with each other.

Sanjay Manohar:

And just in response, if I may. [Group laughing] Actually, you know, we see about 10% of our patients who are amyloid-positive either in CSF, plasma or in PET, they don't progress to get Alzheimer's disease. So, there's a, I don't know if you want to call that a protective factor or some kind of resilience component, but yes, you can tell someone they've got the pathology but not have the progressive disease or the dementia. And we do that sometimes, for a few patients who we'll tell that to.

Emma Mead:

Thank you. So, I think we've got time for one more question before we sort of close out, but I will maybe swipe one from the audience. As Sanjay mentioned, there's a great variety of Alzheimer's diseases and heterogeneity. So, are current efforts in therapeutic development too broad? And how should the community approach this efficiently? I'm not sure who wants to take that first.

Michele Hu:

Sanjay. [Group laughing]

Sanjay Manohar:

I do think that people often talk about a lot of researchers working on prognosis and what's the value of this? Yes, we can tell patients how long they're going to survive, but the real benefit of knowing prognosis is in doing clinical trials. If you know, for a particular person tailored to their genes, biology, and other pathologies they have, if you know what the trajectory of their disease ought to be, then that makes all these clinical trials much more efficient, much, much more efficient. I can't really explain how much variability there is in this condition. There are some patients who've gone for 10 years after diagnosis. Others for two.

And if your measure is how long people go on for when you give them a treatment, you're going to need an enormous sample size. But as soon as we're able to pin them down to a particular trajectory based on maybe their premorbid MRI, their cognitive function, their particular profile of deficits, and some biomarkers and so on, then we can then use this sort of residualized benefit in the trial. And I think that that's something that is underexplored and people don't like putting into trials really very much. Right? That's my feeling.

Michele Hu:

Yeah, I think we don't... I mean Alzheimer's and Parkinson’s; they're complex neurodegenerative conditions. They progress quite slowly over decades in general. And there are these extremes of phenotype and heterogeneity. But I think we've been too simplistic thinking that we just do a drug trial of one drug versus placebo. 'Cause for cancer, we never do that. Usually, you're needing two or three different medications and then over a period of time, there'll be a repeat staging, scans, and different therapeutic regimes. I think that's the first thing.

And I think the individualised trajectory can be best achieved through assessing the patient in their own home and much more frequent granularity of measures over time, which we can achieve at low cost with digital data. So, I think that and maybe having a trial design where you have a six-month run in where you then establish that patient's baseline before then randomising might make a really big difference. And you also want to know that there is going to be some patient that respond very well and others that don't, and how are you going to then look back to see what best predicted that response. So, target engagement biomarkers, I guess.

Emma Mead:

Thank you very much. We are coming up to time now, and there are still lots of questions, so thank you so much to everybody for sending in questions and hopefully there can be some more discussion a bit later. But I would really like to finish up by a little quick-fire question to everybody. What do you think will create the biggest impact in the way we treat and manage dementia? So, I'd like to go to Peter first.

Peter Johnson:

So, I'm really interested in what you were saying about the digital era and the ability to support people in their own home. I think that would really make a difference. Certainly, in terms of like as these disease progresses, you've got the issue with any change of routine. Anything that's unusual is really distressing and can actually have a very negative effect. The idea of having digital tracking that monitors them, that gives you the ability to make some sort of decision about treatment without drawing them into hospital, drawing them into clinic I think would be very helpful.

Emma Mead:

Thank you very much. Laura, we'll turn to you next.

Laura Winchester:

It's a really big question. I was hoping you would come to me last. [Laughs] So I don't know. I think 'cause we were thinking about trials, and I think in terms of just my particular field, I think everyone will have their own answer on this. And I was thinking about data accessibility. And I think there's a really important thing now where we are thinking we have these trials, we have things ongoing, but then the data is locked away afterwards. And I think it would be really useful for onward if we were able to access and work with that data in the community. So that's my one thing, but I think there are others.

Emma Mead:

Thank you very much, Laura. Sanjay, we'll turn to you.

Sanjay Manohar:

So, it's a controversial answer. If you break your leg, you can fix it, get a new one. Your brain is you. It's your personality. And until now, there's been nothing in the universe that can do the same thing. But now, assistive technology and things that can supplant, you know, help you with your memory, on the horizon with AI. And although you can't replace a person, the identity, these devices, these algorithms are quite good at emulating particular people given the amount of training data you give them. And there may be ways in which AI cannot be a brain replacement but can kind of facilitate thought.

Emma Mead:

Fascinating. Thank you very much. Michele.

Michele Hu:

Just very practical. I think we may need collaboration, real collaboration between hospital care and community care and the patient. And I think community care could be better streamlined. And we would save so many blocked patient bed days if we had a way to discharge patients that needed it sooner into the community, into the appropriate places with support.

Emma Mead:

Wonderful. Thank you so much. Lots of different perspectives, and it's been wonderful to hear your thoughts and comments. So, thank you so much. And I'd like to thank the audience for all the questions that you've submitted and thank everybody on the podcast for listening. And please join me in thanking the panel members. [Audience applauding]

That's where we'll leave it. My thanks to Sanjay, Michele, Peter, and Laura, and to everyone who was there on the day. You can find more conversations like this one at Dementia Researcher wherever you get your podcasts. Thanks for listening.

Announcer:

The Dementia Researcher Podcast was brought to you by University College London with generous funding from the National Institute for Health and Care Research, Alzheimer's Research UK, Alzheimer's Society, Alzheimer's Association, and Race Against Dementia. Dementiaresearcher.nihr.ac.uk.