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When people hit 50 years old, you can have a health check, you have your cholesterol measured. We'd really like to see something parallel in Alzheimer's disease, and then we can maybe give them a treatment that would be preventative. Hello, and welcome to Instant Genius, brought to you from the team behind BBC Science Focus. I'm Jason Goodyer, commissioning editor at BBC Science Focus. In today's episode, we're joined by Professor Selina Ray, a neuroscientist based at University College London, to talk about the latest research in the fight against dementia. So, Selina, welcome to the show. Thanks so much for joining us.
Thank you for having me. Oh, it's great to have you here. So, today we're talking about dementia. So, this is a condition, no doubt, everyone watching will have heard of. But they likely won't know that there are many different types of dementia. So, I think maybe the best place to start is, can you just run us through that, please? Absolutely. So, there are almost 1 million people in the UK who are living with a type of dementia at the moment. So, it's a condition that is really common. Um, but dementia is actually an umbrella term which describes a collection of symptoms. So, most people, when they think of dementia, might think of memory loss, but there are other symptoms such as confusion, problems
understanding or using language that can be associated with dementia. [snorts] Now, dementia is caused by different diseases of the brain. The most common cause of dementia is Alzheimer's disease. And this is why sometimes dementia and Alzheimer's disease are used interchangeably. Um, but there are other causes of dementia such as vascular dementia, dementia with Lewy bodies, and frontotemporal dementia. And they differ in the types of pathology in the brain, so the changes that are happening, um, but also the regions of the brain that they affect. And so, each underlying cause of dementia can result in a slightly different combination of those symptoms.
Right. So, you're you're a neuroscientist, obviously, so you study the brain. So, what's happening in our brains when we do, you know, suffer from dementia? So, dementia is caused by the death of a particular type of brain cell called a neuron. And as those progressively die over time, that's what results in the different symptoms that we just described. And depending on where that cell death is happening in the brain, will depend on which particular symptoms manifest. So, for example, in frontotemporal dementia, it's the frontal parts of the brain that are affected, and that is then more associated with changes in language and behavioral changes, for example. Now, if we take a little bit of a closer look in
the brain, what we see in common across all types of dementia is the accumulation of build-up of protein aggregates. And the type of those of protein which is building up differs between the different diseases. So, perhaps if we use Alzheimer's as an example, because it is the most common type, what Alois Alzheimer himself observed under the microscope back in is the build-up of two different types of protein pathology. The first is called amyloid, and it's made of a short peptide called amyloid beta, and this accumulates outside of the cells. And the second pathology is what we call a neurofibrillary tangle. That's made up of a protein called tau, and that happens inside the cells. Now, the
relationship between those proteins and cell death is something that we are still actively investigating as a field, but the consensus is really having the build-up of this protein in brain is not a good thing, and ultimately will result in the death of neurons and the symptoms of the different diseases. So, it sort of typically occurs in older years. So, you know, why is that? So, this is something that I think is really interesting. Now, one of the challenges in dementia research has been defining when does the disease start? And we would typically think of disease starting when somebody presents with symptoms. But actually what we now understand is the changes in the brain
are happening maybe 20 or 30 years before somebody presents with their first symptoms. Now, this is fascinating because it suggests to us that the cells in the brain can cope with a certain level of the pathology, but after a certain amount of time, it causes the cells to become dysfunctional and eventually die. And so, we've had really good insights into this by studying people who have rare genetic forms of Alzheimer's disease. Now, the majority of Alzheimer's disease is what we call late-onset and sporadic, but in a very rare number of cases, if a parent has Alzheimer's disease, their children will have a 50/50 chance of also developing it because they carry a faulty gene. Now, studying those
individuals has been really informative to us in the field because if we know somebody has a gene which will cause them to develop Alzheimer's, we can actually study what's happening in their brain far in advance of them developing their symptoms. And it's through studying those families that we've really been able to understand that the changes are happening really far in advance, but it's not resulting in symptoms until people are later in life. So, obviously as we age, uh um bodies and brains do change. So, how does dementia differ from uh say natural aging? I think this is a really important question and it's something that I think has been misunderstood generally and it's really good to have the chance to
clarify. That um I think for a while there has been a kind of misunderstanding that dementia is people getting older and more forgetful. Um and that's really not the case. Dementia is caused by diseases of the brain such as Alzheimer's disease. As we get older our brains do change and we have now studied the rate at which brain cells are lost in people as they age compared to people who have Alzheimer's disease. What we see in Alzheimer's disease is there's an acceleration in those brain cells dying. So, it's really something that's different from normal aging and that's such an important distinction because if we accept that dementia is caused by diseases of the brain, through research
we can understand those diseases and develop treatments to stop those diseases. Yeah, so let's have a look at um how we do research this then. I think this is really fascinating. I see you know, it's it's something that a lot of your work focuses on. Cuz of course it's very difficult to study the human brain like when somebody's um you know, a lit in a living person. You need all sorts of expensive complex devices to do that. But there's other ways of doing it. There are. So, I started my career actually studying postmortem brain tissue. So, people who had lived with Alzheimer's disease and then had chosen
to donate their brain to science after they passed away. And that's incredibly valuable and insightful to be able to look at the brain of somebody who has lived with the disease that we're working on. But of course that only gives us access to a single snapshot in time, a single time point and generally that time point is at the end of somebody's disease journey. Now I really strongly believe um that if we want to be successful in treating these diseases, we need to understand the first things that are going wrong and we need to intervene as soon as possible. But as you've just pointed out quite correctly, it's really difficult to access living brain tissue during life. So we've learned huge amount from
non-invasive techniques such as MRI and PET imaging. But actually I want to get at the nuts and bolts, the DNA, the RNA, the proteins that make up the cells. So our approach to do this is to use patient-derived stem cell models. And what that means is we use a technology called induced pluripotent stem cells, which gives us the ability to make stem cells from any individual who carries a gene of interest or has a disease of interest and chooses to participate in research. So what we do is we take small bit of skin um about the size of a rubber on top of a pencil. And we do that from people with and without the genes that cause Alzheimer's disease.
We can take those skin cells and we reset the identity of them to make them into stem cells. And because stem cells are essentially blank slates and they become can become any cell type of the human body, we turn the stem cells into neurons. And so that means in my lab we have stem cells from people with and without dementia and we can compare those two cells to understand the things that are going wrong. Yeah, so let's go back to what you're saying about how it can kind of be not necessarily latent but not people can not experience symptoms until you said about 20 years, which is you know, it's just quite surprising. So how sort of
diagnoses, you know, how does that work? It's something that has been quite challenging and if we think back again to the fact that they there are these multiple different causes of dementia, it's not always straightforward to tell somebody during life what type of dementia they have because they don't always fit into neat little boxes. There's kind of crossover between them and that means the diagnosis can be quite challenging. But what we're seeing now and I think it's really an exciting development is the ability to detect some of the proteins that are changing in the brain in a blood sample from an individual. So I mentioned a protein called tau which builds up in the brain of people with
Alzheimer's disease. We're now able to detect a specific form of tau in the blood samples and we can do that before somebody has any of their symptoms. Now this is really exciting because it gives us opportunities for early diagnosis and if we want to give people treatments early on, we need to be able to identify those people as soon as possible. Um but it also eventually may lead to the possibility to do screens in the population. So in the same way now that you know, when people hit 50 years old, you can have a health check, you have your cholesterol measured and if your cholesterol is high, you may be given a statin. We'd really like to see something parallel in Alzheimer's disease where we can measure people's
tau levels, we see that somebody has a raised level of this protein and then we can maybe give them a treatment that would be preventative. Now we're not there yet but that's what the field is really striving towards. So we sort of touched on it earlier but let's have a look more deeply in the progression of dementia comes in sort of stages. Is that right? Yeah, can you tell us how that works? Absolutely. So, I will go back to the protein pathologies, the amyloid and the tau. And as I mentioned, in Alzheimer's disease, we see both of these proteins in the brain at postmortem. But because it's a single snapshot in time, it
doesn't tell us which has come first, and it doesn't tell us which is killing the neurons. It could be both, it could be one or the other. Now, we've had really a lot of insight into this from studying those rare families who have genetic Alzheimer's disease. And we now know that there are three different genes that if you have a mutation in one of those genes, it will cause you to develop Alzheimer's in your early 50s. Now, the three genes are called APP, presenilin 1, and presenilin 2. And without going into too much detail, what we know is all of those genes are associated with the development of the amyloid plaques. So, that starts to give
us a sequence of events because it tells us that the plaques are happening first, and the tau tangles are happening downstream of those plaques. Now, that has been transformative for the field. We those genes were discovered in the early 90s, and it means that a lot of therapeutic um development in the field has been aimed at stopping that amyloid buildup or clearing amyloid from the brain. But what we actually realize is that although that is a really viable therapeutic mechanism that I think we may talk about in more detail, the tau protein is still really important. And what we now know about tau is that it has a much
closer correlation with how severe somebody's dementia symptoms are than amyloid does. So, some of this is happening pre-symptomatically. Individuals will then move into a phase called mild cognitive impairment where they have some mild symptoms, and then as those symptoms worsen and progress, we will then talk about people as having really manifest dementia. And so, the precise combination of therapies that we would aim to give someone very much depends on where they are in that dementia journey.
Yeah, so let's let's have a look at some of the current therapies then, you know. What are they? Are they sort of, you know, oral medicines, injections, and things like that, you know? How What are some of the current treatments? So, this is a landscape that is really rapidly changing, and that's really exciting, but it also means that what I say now, in 6 months, will probably have been updated again. So, at the minute, if we talk about the UK situation, and we talk about what's available on the NHS, the only treatments that people with Alzheimer's disease will receive are symptomatic treatments. So, there are some treatments which will improve neuronal function, and they are only effective in the early stage of a
disease. They don't do anything to modify the disease progression, and when I say that, I mean they don't slow down the progression of the disease. They just alleviate the symptoms. Beyond those treatments, it's mainly non-pharmacological interventions to support people living with dementia as best we can. Now, I said that the landscape is shifting, and in the last few years, we've seen the first disease-modifying treatments for Alzheimer's show success in clinical trials. Now, all of those treatments are targeting amyloid buildup in the brain, and they all um we call monoclonal antibody therapies. So, they are antibodies which recognize amyloid and
in doing so, they send a signal to our kind of clearance systems to remove that amyloid from the brain. Um now, these are not straightforward treatments in several ways. It's It's been a hugely exciting development in the field to show that we can slow down the progression. However, once again, they are only um really effective in people who are very early in their dementia diagnosis. We think that's likely because once the tau build-up started, removing amyloid will have limited impact. Um they also in some individuals come with quite severe side effects. Um So, for example, amyloid can also build up in the blood vessels and if that's the case for a particular individual, the antibody can actually cause damage
to the blood vessel and that results um in kind of micro bleeds in the brain. They're also very difficult and expensive to deliver. Um so, they have to be delivered by infusion by an IV and they require um follow-up through brain scans just to make sure that they're not um causing these side effects in individuals. So, we have a bit of a balance in that they are really exciting and it's moved the field forward in terms of disease progression, but actually they're currently not available on the NHS in the UK because the cost-benefit analysis that is done to approve new drugs currently says the benefits don't outweigh the risks and the costs.
However, they're putting us on a journey where we now know disease modification is possible and they're just a start, right? I think this field is really accelerating. I'm actually just back from an international Alzheimer conference where we've been hearing about the next phase of trials um targeting tau, which is very exciting, but also using these initial findings from amyloid therapies to say how can we improve on this? How can we use the same approach, but make it more effective and reduce the risk of those side effects? So, sort of what would those, um, what would those therapies look like? Would it be, you know, how are they administered? So, there are a couple of really exciting developments that I will share.
Two, maybe starting with the amyloid antibodies that I just spoke about. So, one of the challenges for any brain disease is actually getting therapies into the brain in the first place. Um, because we have a blood-brain barrier, which is there to protect our brain from things entering that shouldn't be there. Um, but there's also a physiological way where our brain can transport things across the blood-brain barrier, because sometimes things need to get in and out. And so, what is happening now is a company's taking those amyloid antibodies and actually hijacking that pathway. So, using the brain's natural transport systems to deliver things across the blood-brain barrier. Now, that has several benefits. It means that
more of the drug gets in. It reduces the risk of side effects because we're taking advantage of our natural physiology to get those drugs into the brain. And it also means the process of clearing amyloid therefore becomes much more efficient and much more rapid. So, that's the first, um, exciting development. The second one is a change in how things, um, how antibodies are delivered into the brain, how these treatments are given. So, currently these antibody therapies are given by monthly infusion. That has to be done in a specialist center. Um, obviously becomes geographically limiting and more expensive to do that. But, what we've just seen in the USA is that the FDA has approved subcutaneous administration of these antibodies. That
means it can give them be given by injection, which opens up the possibility for self-administration um rather than it needing to be done in the specialist centers. And if I could just mention um one final development that I think I'm really excited by, it's important that we look beyond amyloid as a target. As I mentioned and amyloid is likely to be most successful when intervention is early and before other changes in the brain such as tau pathology, neuroinflammation have started to happen. Now, there are some really exciting um phase two and phase three trials going on in the kind of therapeutic space targeting the tau protein, but also targeting some of the response um pathways in the brain such as neuroinflammation. And I'm really excited to see what the
results of those will be. And if we look kind of 10, 15, 20 years from now, what I think we will be doing is looking at somebody where they are in their dementia journey and giving them a combination of therapies in a bespoke way depending on whether they are at the beginning or more advanced in their dementia journey. Yeah, so like looking at even further forward, so we've established the fact that the neurons are degraded thanks to this condition. And you mentioned stem cells there earlier. So, is it possible that we could find a treatment eventually that could even reverse the damage and how the damage that has been done sort of re-grow or redevelop?
I think this is a really fascinating question and my answer will be in several parts. I think first of all, this is really a challenging approach because in Alzheimer's, the damage to the brain is so widespread. So, actually by the time um we work with postmortem tissue, for somebody who has lived with and died with Alzheimer's, their brain will weigh a third less than somebody who hasn't had Alzheimer's. So, that just gives you an idea of the extent of the cell loss throughout the brain, and replacing those neurons and having them connect kind of signal to each other in the way that they should do, I think is a huge challenge. But, that doesn't mean it's impossible. And actually, if we look to
other disease areas such as Parkinson's disease, um there have been some really exciting developments there where cell therapies are in trial and showing great potential. I hesitate to use the word easier in Parkinson's disease because none of this is easy, but I think what gives that approach an advantage in Parkinson's disease is at least at the early stages, the cell loss is more localized to a specific brain area. So, actually there replacing those cells um can be a little bit maybe more accessible than trying to replace cells throughout the brain. Um but, if I may extend that answer, there still has been value in studying this approach in Alzheimer's disease. And some groups
have tried cell replacement in mouse models of disease. And actually, what they found has been really interesting. It the mouse improved in certain tests of cognition and memory that we can do for mice. But, it actually wasn't through cell replacement. It was through those cells the transplanted cells secreting factors that nurture the cells that are still alive in the mouse brain. So, even though that hasn't led to cell replacement trials, it's really informed about how we think about treating the disease and whether kind of nurturing this the health of the remaining neurons can also be a viable strategy. So, there's still a lot of promising avenues to explore then.
I think it's a really exciting time in Alzheimer's research and we've really seen the kind of energy of the field shift in terms of our increased understanding of the biology, but also now this excitement around early diagnosis and disease-modifying treatments. And although that is really exciting, we do still have a long way to go. As I mentioned, those treatments are working only at the early stage of disease, only in a certain subset of people, and you'll notice as I've been talking, I've kind of focused on Alzheimer's disease. There are other causes of dementia, as we mentioned, things like frontotemporal dementia that also we're seeing really rapid progress, but Alzheimer's is the main area of
investment because it's the most common disease. Those other causes need better diagnosis and better treatments, too. So, very exciting, but still a long way to go. Thank you for watching this episode of Instant Genius, brought to you from the team behind BBC Science Focus. That was Professor Selina Ray. If you liked what you just saw, then please do consider liking and subscribing to the channel.
