Instant Genius - How dementia affects the brain, and how we’ll one day beat it

Episode Date: August 17, 2023

According to the World Health Organization, dementia currently affects an estimated 55 million people worldwide. But despite its prevalence, there is very little in the way of effective treatments. In this episode we catch up with Tara Spires-Jones, Professor at the UK Dementia Research Institute at the University of Edinburgh and President of the British Neuroscience Association. She tells us all about the different types of dementia, how they progress and the latest thinking on how we can beat the disease once and for all. Learn more about your ad choices. Visit podcastchoices.com/adchoices

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Visit name audio.com to learn more. Hello and welcome to Instant Genius, a bite-sized masterclass in podcast form. Each week you'll hear world-leading scientists and experts talking about the most fascinating ideas in science and technology today. I'm Jason Goodyear, commissioning editor at BBC Science Focus magazine. According to the World Health Organization, dementia currently affects an estimated 55 million people worldwide. But despite its prevalence, there's still very little in the way of treatments. In this episode, we catch up with Tara Spires-Jones, professor at the UK Dementia Research Institute

at the University of Edinburgh and president of the British Neuroscience Association. She tells us all about the different types of dementia, how they progress, and what the latest thinking is on how we can beat the disease once and for all. Let's kick off first with looking into what we are talking about when we talk about dementia, because it's not a single disease, is it? That's exactly right. So dementia is the umbrella term for a set of symptoms that people. experience. And you've probably met someone with dementia. Most people have because it's so prevalent.

But the symptoms are this progressive loss of cognitive function. So it often starts with memory impairments, sort of forgetting where you left things or some spatial memory like where you park the car. But eventually the diseases that cause dementia spread through the brain and more and more cognitive functions are impaired. So at the end stage, it's really actually very sad. At the end stage you can't move or talk or, of course, recognize your loved ones. So let's have look at the different types then because I think a lot of people may have heard of Alzheimer's or perhaps of vascular dementia, but there's also frontotemporal dementia and things like this. So can you go through those and tell us what the difference is and, you know, how common they are in relation to one another? Yes, I mean it depends on how much time you have. I have lectures of hours worth of the different kinds of dementias. But those core set of symptoms that we were just talking about of this cognitive decline can be caused by lots of different underlying pathologies. in the brain. As you mentioned, the most common form of dementia is Alzheimer's disease. It's thought to account for over half, approximately 60% of people with dementias will have underlying Alzheimer's disease

pathology. I should say that these exact numbers aren't always agreed in the field because the human brain is amazing and wonderful and messy, right? So you can have Alzheimer's like pathology, but you can also have vascular pathology. So you also mentioned vascular dementia, which is a type of dementia that's caused by changes in the blood vessels in your brain or damage to them. There are frontotemporal dementias, which all on their own are quite complex because there are lots of different subtypes of this, but the frontotemporal means that the frontal part of your brain and the temporal part of your brain are degenerating, and that causes symptoms that are a little bit distinct from more classical Alzheimer's symptoms. So Alzheimer's disease starts in the part of the brain

really important for memory, in the medial temporal lobe. But in frontotemporal dementia, that frontal part especially, that's the part of your brain that controls your behavior and your inhibitions. So you can have some very difficult behavioral symptoms with frontotemporal dementia. People can change personality and sort of say things that they wouldn't have normally said. And that's really the underlying disease. So let's see. What else have we got? Dementia with Louie bodies is another type of dementia.

And that's very closely related to Parkinson's disease because the same kind of pathological protein clumps up in the brains in both Parkinson's and dementia with Louie bodies. But there are, I mean, the list of diseases that can cause dementia is very long. So you can have something called chronic traumatic encephalopathy, which is a disease caused by, they used to call it dementia pugilistica. So that's when you boxers would get dementia from head trauma, for example. So I won't go through all of them because I think we could be our full half hour talking about all the different clinical manifestations of different dementias. What are some early warning signs then that people should be looking out for in themselves and in their friends and family members? That's a tough one because most of us as we age will undergo age-related changes in our cognitive abilities that are not caused by one of these diseases that will progress into dementias. So typically early signs of dementia's are problems with your memory or thinking, but only 50% of people who have self-reported problems with their memory would call mild cognitive impairment or self-reported problems with their thinking. Well, only about half of those people will go on to develop dementia. So it's really a tough one. I would honestly say I'm not a medical doctor for special

preface this, but I wouldn't personally worry about it if you're a little bit older and you have some slight issues with your memory. I would try not to worry overly about it if it were me. When it becomes problematic is when these things progress and start getting worse and worse, I would say. So perhaps another tough question. What do we know about what age dementia typically begins? I mean, can we say anything about that? Well, there are lots of different kinds of dementias and they have different. typical ages of onset. And even within the most common form of dementia, Alzheimer's disease,

we classify it as late onset or early onset. So early onset is typically defined as earlier than 65 years of age. So earlier than 65 years of age would typically be classified as early onset. And some early onset dementia is run in families. So they're caused by a gene mutation. And then in Alzheimer's disease, people with an onset after 65 are considered late onset or more sporadic forms, which aren't typically caused by gene mutations. So most of these dementias are age-related, so your age goes up the older you get. But there's not a real precise age that you could say for all dementias would be the commonest age of onset. I suppose we could calculate it, actually, but I don't know it if there is one that people would to use.

So obviously we're talking about something incredibly complicated here then. So how is dementia diagnosed? So dementia diagnosis and keeping in mind that I'm a neuroscientist working in a lab, So this is not what I do day to day, but people who have problems with their memory or think they might be in the early stages of dementia can go and see a specialist. They can go to their GP. They can go see a specialist. And there will typically be a series of cognitive tests that you might do. We're getting more and more advanced in terms of there are what we call biomarkers that are in development. So there are now tests that you can run on cerebral spinal fluid. So you have to have a spinal tap for that. And that's not very common. There are tests that you can run with a brain scan called a PET scan. which involves injecting a small amount of radioactive tracer and putting you in a scanner. And again, this is very expensive and is not done in a clinical diagnostic setting, but is used for research sort of clinical trial settings. And we're getting closer and closer to blood tests that can give you an idea about whether

you're at high risk. They're not perfect yet, and they're not, as far as I'm aware, in routine clinical use in Britain. In the U.S., I think there are blood tests that can be done now, but they don't give you a definitive answer. They give you sort of an idea that you might have some of these pathological proteins in your brain that cause Alzheimer's disease. So you touched on it slightly there, you know, as a neuroscientist, how did you go about studying dementia, you know? What's your

kind of day-to-day look like? So in my lab, we're trying to understand the fundamental brain changes that cause these different types of dementias. We do a lot of work on Alzheimer's disease. And one of the things that we're most excited about and that I've been fascinated by since I was a graduate student is synaptic connections. So I don't know if you've heard of these, but your brain is made of lots of different cell types. The neurons are the cells that fire in the network to help you with thinking. They're the ones that do the work. And the neurons talk to each other via these synaptic connections. So you have 100 billion or so neurons in your brain, and they talk to each other through 100 trillion or so synapses. So this is a phenomenally complex

system that's more synapses in your brain than stars in the Milky Way. So this is a beautifully complex system. And the wonderful thing about synapses is that they're very important for thinking and learning and memory. You make new synaptic connections and they get stronger as you learn and they weaken your synaptic connections as you forget things. And these are very hard hit in Alzheimer's disease. So you can imagine a disease of memory is going to be severely affecting the synapses. And of all the things we can measure in the brain, and we haven't really talked about these yet, but you have these pathologies in the brain. And of all the things we can measure that goes wrong in the brain, the loss of these synaptic connections is the strongest predictor of cognitive decline in Alzheimer's disease. So in our lab,

we're looking at what's happening to these synapses? Why are they dying? What's going on inside them? And we've developed some high-resolution techniques to look inside individual synapses and human post-mortem brain tissue. And we've seen that you get tiny clumps of the two pathological proteins that have been used for a century to define Alzheimer's disease. They don't only clump up in these big aggregates that we've known about for decades and centuries, but they also accumulate and small amounts inside individual synaptic terminals where we think they're causing damage and causing this synaps. So that's one of the things we work on. And I'll try not to keep talking because I could literally talk about our lab work for hours.

No, that's great. So what else can we say then? I guess what does a brain with dementia look like? How can we say take a scan of it and say that person has dementia? So there's several different ways you can look at a person's brain while they're still alive and get some really good indications that they probably have Alzheimer's disease is the one we're most advanced on. The most obvious thing you can watch, if you can get someone in a scanner over time, is you can actually watch the brain shrink. So common to all these dementias, they're all what we call neurodegenerative. That means neurons are dying, and as the neurons die, the brain is shrinking. So you can watch over time the brain shrinking.

And depending on where the brain is shrinking, you can start to classify what type of dementia it probably is. The hippocampus, which is this small part of the brain really important for memory, gets smaller in Alzheimer's disease. early on. The frontal and temporal lobes get smaller in front of temporal dementias and things like in Parkinson's disease, you have different parts of the brain are degenerating. So we can look at the brain degeneration. But we can be a little bit more specific than that now with more sophisticated scans. So you can actually inject a pet tracer, which is positron emission tomography, this tiny radioactive molecule. You can inject pet tracers that are specific for different types of aggregates. So now we can inject an amyloid pet tracer into people. And we can see if you have

amyloid plaques, which is one of the classic pathologies of Alzheimer's disease. And there are pretty good pet tracers for tau now. The other type of pathology that clumps in Alzheimer's patient brains is tau, neurofibrillary tangles. So tau is an interesting one. And we can do pet scans to see if you have tau pathology. But tau is not only an Alzheimer's disease, but we are also a whole host of diseases called tauopathies, which have tau pathology without the amyloid, and they cause different kinds of dementias. So some frontotemporal dementias can be caused by tau pathology. You can have diseases like progressive supernuclear palsy or cortical basal degeneration that are caused by this tau clumping in the brain. And based on whether you also have amyloid or where the tau is showing up in the brain, we can

start to get another idea of which type of dementia or which type of neurodegenerative disease you might have. So what do we know about how big a role genetics play in our risk of developing dementia? So that depends on which type of dementia. So genetics play a big role in some of these dementias and a small role in others. So if we start with Alzheimer's disease, since it's the most common cause, there are very rare familial forms of Alzheimer's disease that you inherit from your mom or your dad. They are caused by mutations in genes that are causing that amyloid pathology to clump up. So you can have a mutation in the amyloid precursor protein,

which is the big long protein that's then chopped into the little amyloid that sticks in the plaques. or you can have mutations in presynylins one or two, which are enzymes that chop the APP into the A-Beta, and those cause Alzheimer's disease, the early onset familial forms that you can inherit. But of Alzheimer's disease cases, those are less than 5%, probably somewhere closer to 1%. So the vast majority of Alzheimer's cases aren't caused by familial genes that guarantee you'll get the disease. However, there are what we call risk genes. So there are a whole host of genes that can increase your risk of developing dementia, but aren't a guarantee. The biggest one of these is called APOE, apolypo protein E, epsilon 4. So you've got

three different types of APOE gene in humans, two, three, and four. And the E4, APOE4 gene, increases your risk by threefold if you inherit one copy of it, and by over 10fold if you inherit two copies of it. So that means that if you combine the risks of aging and APOE4, by the time you get into your 80s, if you have an APOE4 gene, you are very likely to have Alzheimer's disease. So you have these genes. that can really drive up your risk. And there are common genes that can increase your risk a little bit. And it's quite difficult to give a precise number for me. Genetics is not my field.

So I don't know the exact proportion of Alzheimer's cases where we think genes played some role. But what we can do now is say we can give you a polygenic risk score. People can look at the geneticists can look at all of your genes and say you have this group of genes that means your risk of dementia is higher than average or lower than average. So that's being done. And it's really fascinating for research, for neuroscientists, because these genes have given us clues about what's causing the disease.

So the amyloid cascade hypothesis, that amyloid, the causative genes, really drove the field for decades. And now we actually have drugs that can attack amyloid and slow disease progression. These are very recent. But beyond amyloid, the other host of genes that change your risk are largely expressed in cells in the brain called microglia and astrocytes, which aren't the neurons, but they're these immune cells and support cells. So that's taught us that it's not just the neurons that are important in this disease. We have to look at all the different cell types. And there's some fascinating research going on into how we might get at some of these early stages of disease that are more mediated by these other cell types. Ambition comes in all shapes and sizes.

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So you know what sort of things can we do or not do to lessen or greater in our risk of developing dementia? Yeah, that's a great question. So lifestyle factors are thought to play a fairly large role in the risk for developing dementias. If you look at what we call all-cause dementia, where we don't worry so much about the exact brain disease underlying, but we just say, do you have a dementia diagnosis? The best estimates are that about 40% of people with dementia could have prevented that with changes in lifestyle factors, which is a pretty stunning number. If you think about the number of people living with dementia worldwide, which is

over 50 million, if 40% of those could have been prevented by lifestyle changes, that would make a massive difference to not only the people living with dementia but of course our public health systems. So to your question of what can we do, it's actually pretty common sense and what most people would have told you to do beforehand to keep your heart healthy. So things that increase your risk of dementia are things like a sedentary lifestyle, being overweight, smoking, sort of all the things that are bad for your heart and blood vessels tend to increase your risk of dementias. The things that are a little bit more new and a little bit more specific to your brain and not just your global health and your vascular health as well as your brain

are social isolation and hearing loss have been associated with increased risk of developing dementia. So these were found, this is what we call epidemiology, where scientists look at huge populations of people and say, if you were socially isolated, was your risk of dementia higher or lower than people who weren't? And that can be very informative, but you have to understand that there's a limitation to this type of thing, because we can't determine from this type of study whether the social isolation causes dementia, whether early stages of dementia cause you to isolate yourself or whether there's something unrelated, right? So it can't prove causality. But there's quite a lot of data from different studies indicating that those things are at least associated with an increased

risk of dementia. Things that are associated with the decreased risk of dementia are almost the inverse. So a healthy lifestyle, eating well. Staying in education is actually very protective. So the longer you have stayed in formal education, the lower your dementia risk. And I think that one's fascinating because it comes back a little bit to the synaptic connections we were talking about. We think you're building a big, robust network that can resist the pathology and the brain for longer. So education and keeping both physically and socially and mentally active. So there were some recent data that are quite interesting. I got a call from another journalist about,

do you think we should play chess? The Prime Minister suggests we need to be a chess nation to protect our brains. And while there's only a few studies that have directly looked at this type of thing, overall the weight of evidence does suggest that keeping mentally and physically and socially engaged is probably very good for protecting your brain as you age. So let's move on then to now, so once dementia has been, diagnosed. Currently, how do we go about treating it? So up until very recently, there was nothing we could do for people with a dementia diagnosis that could slow the disease. We've had for a couple of

decades several different treatments that help the symptoms, and most of these were targeting something called acetylcholine, so they were colonesterase inhibitors, and they boosted the amount of acetylcholine that stayed in your brain, and that helped make you feel a bit better. It helped reduce your symptoms a little bit, but what they didn't do is they didn't slow down this insidious progressive cognitive decline and the progression of the disease through the brain. Very recently, only in the last couple of years, drugs targeting the amyloid protein, amyloid peptide, have been approved in the U.S. And these have been shown in face-through clinical trials, so there have been a couple of different drugs now that have passed their long, long clinical trial period,

and they had very similar results, that if you put in an antibody that recognizes amyloid, it slows the progress of the disease by about 30%. And that's not a lot, right? We would love to have something that stops the disease and makes you even better if you could. But what it does is it actually slows the disease progression. So that's phenomenal for giving people hope that we can at least slow this disease. So you mentioned there something called a Cetacolene.

Could you just give us a brief overview of what that is and how it affects people with dementia? Yeah, so this is based on some fairly old science. So, for example, in Parkinson's disease, what's known is the neurons that produce dopamine in the substantial nigra die. And if you replace the dopamine, people feel a bit better. That was well-established for Parkinson's. And in Alzheimer's, originally people thought a very similar thing was happening with colonerging neurons, that neurons that produced this neurotransmitter called acetylcholine were dying,

and that if we replaced the acetylcholine, people would get better, and the disease progression would stop. While it's true that you do lose those neurons, you're also losing the rest of your neurons. So it wasn't sufficient to stop the cognitive decline. And what we've learned more recently is that all the synapses and all the neurons pretty much in the network are vulnerable and are dying. So we needed to go and attack something earlier on. We can't just replace one neurotransmitter. We have to stop the damage.

And that's what we're trying to do with things like the amyloid directed therapeutics is remove the toxic protein and stop the damage to the brain so we could slow the disease progression. So a phrase you often hearing medicine is that prevention is better than cure. So I think what I've done some reading about and I thought was a really interesting idea. was how to stop dementia from arising years before symptoms are even present. That's a great point. So what we know about Alzheimer's disease, and we think probably common to several other types of dementia, is the changes in the brain start decades before you have symptoms. So it's important that we think about our lifestyle factors.

If we could prevent 40% of dementias by leading healthier lifestyles, that would be good for all of us. But we also don't want to blame the 60% of people who couldn't have prevented their dementias, right? So we'd like to be able to prevent or treat dementia and everyone. So other types of prevention that have been considered are things like vaccines. It would be nice if we knew who was at high risk and we could vaccinate them against these pathologies so they wouldn't develop. There was one trial of an active vaccine. It didn't work.

It actually, some of the people who were in the trial didn't have Alzheimer's because this happened before we had these better biomarkers and scans. So that mucked up the trial a bit. But it's also, you know, maybe from the more recent trials we've seen, it's potentially unsafe at a large level, a large scale level, because these amyloid directed therapeutics have some rare but serious side effects. So at the moment, we don't have anything that can fully prevent Alzheimer's disease or the other dementias. But you're quite right, it would be amazing to be able to prevent these diseases or stop them early enough that you wouldn't have symptoms. Because

in that couple of decades, while your brain is developing pathology before you have symptoms, your brain is just able to make up for the damage that's ongoing. Your brain is absolutely amazing. We have what you call plasticity. So if you have a little bit of damage, your brain can just make up for it. Like if you imagine people after a stroke, you might have met someone who had some difficulties with moving a part of their body, but with rehabilitation, they can get some movement back. And that's not because the brain cells came back. It's because your brain can rewire and make up for the damage. So if we could stop the damage early enough, you'd be able to lead a perfectly normal life, we think, and not have that progressive decline. So it's all about getting it early, not necessarily preventing everything, but getting it early enough to stop the disease in its tracks. Yeah, that's something I was going to ask, actually, as it is a progressive disease, you know, say we are able to develop some treatments that can, I mean, stop its progression, say the next thing then, I guess, would be reversing the progression, or is that a naive question? No, it's not. I mean, ideally, if we could stop the disease process, your brain could

recover a little bit. What's probably not going to be possible is if you're already in advanced stages of disease, so you've lost a lot of neurons and you've lost a lot of function, it would be difficult for your brain to make up for that with the normal plasticity mechanisms, because what our brains are not very good at is making brand new neurons and putting them back in the right place and getting them to wire up. You can imagine you have neurons in your brain on your left side that are wired up. They have a connection that goes all the way over to the right side and connects very precisely to a lot of different cells in the network. And if that neuron dies, it's going to be very hard to get that sort of connectivity back. But if you can stop the massive amount of

of neuron loss, you can make up for some of the loss with the existing network. So as long as we got it early enough, you could not only stop the progression, but your brain could recover a little bit, we think. This happens in mice. So in a mouse model that has the tau pathology, if we stopped the disease by lowering the tau expression, the mice not only stopped getting worse, their memory's got a bit better. So, you know, the mammalian brain can do this to a certain extent. So if we caught it early enough, the hope is you wouldn't only stop the disease, but you might get a little bit better as your brain recovered. One final question then by way of summing up.

How optimistic as a research are you for the future of dementia treatment and research? I'm very optimistic. I've been in the field of dementia research since about 2004, so going on 20 years. And for the first 10 to 15 years, I have to say our annual meetings all over the world were quite depressing. We would see another failed clinical trial. It's always been a fascinating and interesting thing to study, but only in the past few years have we started to see that some of this fundamental neuroscience research that we've been doing all over the world for decades and decades is finally now translating into treatments that are slowing the disease. And I think that these new treatments, even though they're not perfect and they have risks, they really are going to

open the door to hope and more funding. So they bring hope to the people living with dementia, hope to those of us in the labs that have been scrolling away for years trying to come up with ways of helping people with living with dementias, and hope for the funders. because one of the things about dementia research is we've been chronically underfunded compared to other biomedical fields like cancer. And if we have the best minds and enough finance, we will make even faster progress. So I think that those three things, the hope from those three groups is really going to drive the field forward. So I'm very optimistic. That was Tara Spires-Jones, Professor at the UK Dementia Research Institute at the University of Edinburgh

and President of the British Neuroscience Association. Thank you for listening to this episode of Instant Genius, brought to you from the team behind you. BBC Science Focus magazine. The current issue of BBC Science Focus is out now. Pick up a copy wherever you buy your favourite magazines or download a digital copy from your preferred app store. You can of course also find us online at sciencefocus.com. This podcast is sponsored by Name, audio and focal. The texture and emotional depth of music can be lost through digital sources or poor signal. Name audio believes you can have digital precision with analog warmth. Along French acoustic specialist vocal, Name creates high-end audio systems combining innovation with

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