Developments in our understanding of dementia

14 modifiable risk factors account for 45% of dementia cases worldwide. Gavin and Jessamy are joined by Prof. Gill Livingston (UCL) and Prof. Geir Selbaek (University of Oslo) to discuss the 2024 updates to The Lancet Commission on dementia prevention.

You can read the Commission here:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)01296-0?dgcid=buzzsprout_tlv_podcast_lancetdementia24_lancet

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Transcript

This transcript was automatically generated using speech recognition technology and may differ from the original audio. In citing or otherwise referring to the contents of this podcast, please ensure that you are quoting the recorded audio rather than this transcript.

Jessamy: Hello, welcome to this episode of The Lancet Voice. I'm Jessamy Baganal, Senior Executive Editor at The Lancet. And I'm here with my co host Gavin Cleaver. This week, we talked to the lead of the Lancet Standing Commission on Dementia Prevention, Intervention and Care, Professor Jill Livingstone, who is a Professor of Psychiatry of Older People at the Division of Psychiatry, the Faculty of Brain Sciences at University College, London, and Geir Saalbeck, who is a Research Director at the Norwegian National Advisory Unit on Aging and Health and a Professor at the Department of Geriatric Medicine at They've just published an update on the Dementia Commission from 2024, and we were keen to hear all about it.

A brief overview of their key messages. There are two new modifiable risk factors for dementia. New evidence supports adding vision impairment and high cholesterol as potentially modifiable risk factors for dementia to add to the 12 risk factors identified in the 2020 Lancet Commission. These are less education, head injury, physical inactivity, smoking, excessive alcohol consumption, hypertension, obesity, Diabetes, hearing impairment, depression, infrequent social contact, and air pollution.

14 risk factors account for 49 percent that's nearly half of the risk for dementia and modifying them may prevent or delay dementia. The Commission covers specific actions to reduce dementia risk across the life course like the importance of good quality education for all and specific recommendations for those living with dementia.

We hope you enjoy the conversation.

Gavin: Jill, Gail, thank you so much for joining us on the Lancet Voice podcast today. We're really excited to have the latest update of the Lancet Dementia Commission coming out. Perhaps we could start with just a kind of really broad overview. What are the main changes in this latest update? Because for listeners that aren't familiar, it's a standing commission that has regular updates.

Gill: So one is in prevention and risk reduction to reduce people's chance of ever developing dementia. The second is in detection and diagnosis of dementia and particularly thinking about biomarkers. And the third is in treatment of dementia, which includes new drugs, but also more evidence about psychosocial interventions.

Geir: I would say that a big change this time was that it was more difficult, because in a way you could say that it has had more has happened over the past four years in this field than during the previous two years. 20 years. So when we try to reach consensus now, we have to innovate a knowledge that the field might be different tomorrow.

And also, Jill talked about the prevention. I think one big change is that we have a lot more knowledge about the interventions, because earlier we have been talking about associations. We say that if you smoke, you're at risk of getting dementia increases. But this time I think we have added a lot of information about that stopping smoking, for instance or reducing air pollution, treating depression, treating hearing impairment or vision loss also works.

Which I think is great evidence or a great message to put through to the people. 

Gavin: The commission was one of the first big works to talk about prevention in, in, in dementia. So you say there's been lots of progress in the last four years versus the previous 20. Do you think there's a kind of bit of a virtuous circle about that?

You're getting the word out of there about these are things you can do to prevent dementia. And then it's following on from that. 

Gill: What one of the members of the commission said is that you publish it and then the dementia community says, go. We say, we know this is really good.

And then the research community said, but we don't know this. And research community says, fantastic. We are going to try and find out. So I think that, the work is partly our work, but it's other people's work as well. And I not only give us huge information to help people and to think about. policy and intervention, but it's really useful for the research community to, as a marker of where we're, of where we're at.

And Gare says it's remarkably hopeful, because for the first time in many of these risk factors, we have more knowledge about interventions, and the interventions have done what we would expect to have happened. The Decreasing excess of alcohol makes people less likely to get dementia.

Decreases, stopping smoking reduces the excess risk. Treating high blood pressure reduces the excess risk. And all of these things are very important and really make a difference to individuals and society in the future. 

Geir: Now I just wanted to add that I think Apart from informing the research environment, this commission is also read by policymakers and clinicians.

So in a way, it sets the stage for what people think is the most important thing. I think I was really surprised by how influential this commission was already in 2017. And I think this has only increased through the last commission and hopefully also by this new commission. 

Jessamy: Yeah. Thanks so much.

I just wondered whether I might just ask, because obviously the risk factors are a really key thing for the commission. And they're what, we all talk about and know, but for our listeners who might not be familiar with the commission, Those risk factors and the associations, as you say, are obviously estimates.

How do you find those risk factors? And to what degree can we have confidence in the sort of magnitude of the relationship between those risk factors and later dementia? 

Gill: Can I start off with the magnitude? So the way we worked out the magnitude is we look at the worldwide relative risk of any risk factor, and we do that through systematic reviews.

However, we know that is, as you see, an estimate and that's worldwide, and they do vary between countries. And equally, we looked at the worldwide prevalence and incidence, and we used the best and most recent data available to try to do that. So we put these together and then we estimate what we call potential the population attributable fraction.

So how much of how much difference it would make if you could get rid of the hold of the risk factor. We consider that people are not at all like laboratory mice, and they tend to have more than one thing wrong with them, and they cluster their risk factors. And so we look at a sample population, and we work out how much how much the risk factors cluster.

And we modify the risk data. decrease it because the person who has high blood pressure is more likely to have diabetes, is more likely to be obese, is less likely to take physical activity. And we cluster them according to them. So that's how we, that's how we work out the magnitude. So it's quite.

Difficult, requires lots of time and lots of sums. And it's the best estimate available. But for individual countries if, for example, people have more or less education, that would make a difference. And it, it changes within individual countries. And Gerald talked more about it in a minute. But for this time, last time we used, British data to look at the overlap, but this time, and people having it this time, we use Norwegian data to look at the overlap, and it is very interesting to know how that varies between populations.

We don't really know. We hope that we will find out in future. But And have a look between all the different populations, but the Norwegian data and our huge gratitude from the HUNT study to let us use it is that it had every single risk factor possible to derive already in it. And that was amazing because we couldn't find any other databases in the world.

in the world that we, we don't know, we didn't look at all of them, but we tried pretty hard and we couldn't find any others like that. But Gareth can tell you more about that because they came from he helped us get access to it. 

Geir: Yeah but first I wanted to add because we, everybody's talking about the magnitude or the importance of these direct factors and I look at this figure, which has a really great impact.

It's a bit scary, but it's a bit scary though, because. These are all the estimates and people say this is the magnitude of the risk. No, it's not the magnitude of the risk. It's the risk and the prevalence of this risk factor in, in the society. So when we have hearing impairment and now LDL cholesterol as the most, in a way, important risk factors, this is not about the magnitude of the risk.

It's also about how common these risk factors are. risk factors are. Yeah. And for the HAD study, it was really great that we could use it. And I don't think that they knew that in, when they did this in the 1990s, they, by coincidence, I would say, collected data on all the risk factors that would be included in the Lancet Commission in 2024.

But that's how it is. But also Jill was talking about how we define the magnitude. I think even more important is how we decide which risk factors to include. A lot of people will say, wow why is sleep omitting? What about diet? Shouldn't that be in? So that is where Jill and her group do the great work preparing all these, evidence, presenting them to the members of the commission.

And they have to fight about is this evidence strong enough to be included among these 14 or 12 or whatever it will be next time. 

Jessamy: Oh, let's hear a bit more about that process. That sounds interesting. Jill, maybe you can, I don't know, maybe you can give us an example of something like sleep. 

Gill: So we initially started off, we couldn't work out which ones to use and we used ones in which were in the American policy and the the British policy.

So we just used these and we didn't and then people kept saying why do you not use whatever sleep diet? And so what we've done for the next two, so what we did for this one is I wrote to all the members of the commission and we tried to get people from a very wide spectrum of the world.

And we wrote to them and said, people are suggesting these risks are, is it reasonable that we talk about them and are there any others we want to add? And then we had to list and then we went through them. at the commission. Like Gare said myself particularly Andrew Samolad, Nahid Mukaddam, John Huntley, Kathy Liu and Sgt.

Costa Freida went through them and tried to find as much evidence as we possibly could, and then presented it to people within the commission, and we discussed them, and we discussed, and You at the end of it came to a conclusion. Did it fulfill the criteria? Was it was the evidence consistent? Did it?

make biological sense? Did the problem proceed by enough time that it wasn't caused by dementia? If there was an intervention, which as you said, there's now a lot more, did it alleviate it as we would expect it to? And we looked through all of these different types of evidence and we asked anyone who knew anything else or any other literature to add to it.

And then we discussed it. And then at the end of it, we, I tried to summarize and say, did people just say this? And they said, no, you haven't understood, or yes, you have understood it. They said, no, we kept going until we had 100 percent consensus as to what things meant. And many of the risk factors that are not in may be risk factors.

And we've talked about them in some detail. It's just, the evidence isn't quite there yet. It's not consistent or strong enough. And I play a game with myself now that at the end of it, or just after it's all been presented, I think which risk factors might be in the next one, and I'm consistently wrong.

Geir: But it's a good thing that some of the authors of the most influential papers on, for instance sleep and so on, are members of the commission. So in a way that they are there to tell about and defend their papers. But also I think it's important that in this process we have to rely on not the highest level of evidence because that's impossible.

You mean you can't have a randomized controlled trial, some exposure that happens 20 years before. the outcome. So we have to look at observational data and then see if many different studies goes in the same direction, and whether there also is a mechanistic, in a way, explanation of this association, which is a kind of a jigsaw puzzle, and really important in this, have this thorough consensus process.

Gavin: I was going to say because it must be so difficult to untangle causality from the, from what you're looking at. 

Gill: I think it is hard and that's why we are so if we look at sleep as an example, nearly all of the studies in sleep are in the few years before people develop dementia and dementia, as people are developing it, their sleep gets worse.

It's extremely difficult to disentangle causality. Is the sleep causing the dementia or the dementia causing the sleep? I think it's becoming clearer, but I don't think it's clear yet. The, and we also felt that since the study said that both long and short sleep were associated with dementia, that's not biologically plausible.

It suggests that it's sleep disturbance rather than a cause. But, then if we look to social contact, which my colleague Andrew Summerlad started looking at nearly 10 years ago now, we weren't sure whether, as people develop dementia, they didn't have social contact or whether people who had less social contact were more likely to develop dementia.

And so looking at longitudinal studies and looking backwards and forwards in, in groups of data. What we found is that people don't have less social contact as they develop dementia. It's not causative. What happens is they have different social contact. They what happens is that as they develop dementia, they see more of their families and fewer friends, but they have the same amount of but people who have less social contact in their 40s, 50s and 60s are more likely to develop dementia and that gave us a much clearer idea of causality and then going back to these studies, more and more of them are doing things.

They're doing queasy experimental things, areas, for example, where pollution is reduced. And we find that affects cognition and dementia. And that means, that makes it very much more likely. These are the sorts of things we do. But it is difficult. difficult and it's becoming, but all the time there's more and more evidence and things are becoming much clearer and the hope for the future that we really can do a huge amount about things is becoming, I think much better.

Geir: I think this is a very important point. Because, as we know now, the changes in the brain in Alzheimer's disease starts 20 years before you start losing your memory. So at what stage are these changes impacting on the risk factors? That's a bit difficult. Now with the new blood based biomarkers, I think researchers will be able to follow the development in the brain in association with the development of risk factors.

which can inform this field immensely in the future. So when does this amyloid, beta amyloid, start building up in the brain? And when is the risk factors being measured? I think that will be immensely. And as a matter of fact, we are doing this in the HUD study now. 

Gavin: So perhaps you could tell us a little bit about these biomarkers and what's changed since the last update then.

Geir: I think this is potentially a game changer for the diagnostic process in dementia. But there are a lot of challenges, ethical challenges, in terms of resource. But I live in Norway with a lot of people living in remote areas, the longer distance of hospitals. And if they were to receive a biologically.

confirm diagnosis of Alzheimer's disease, they would have to go to a hospital to have a spinal puncture or an amyloid PET scan. Maybe next year they can go to their general practitioner and get the result with a precision, which is as high as done by a spinal puncture or an amyloid PET scan. There's a lot of things we don't need know about this yet, but I think this is May be as important as the new disease modifying therapies that, precise analysis will be available to a lot more people.

around the world, I would say. 

Gill: I want, I agree with, I agree about that, but I'd like to say a caveat that I think for people who have dementia, I just think that by the time if we do another Lancet commission, nobody will be doing CSF parameloid. I think that it will be blood. The biomarkers, every, It isn't quite there yet, but all of, it's so consistent, the message about how good it is, how good certain markers are at picking up.

I think that's what will be happening, but we shouldn't be scanning, we shouldn't be testing the whole population without dementia, because many amyloid biomarker and never develop dementia. And The majority of people with a positive amyloid biomarker, and that gets more and more as we get older, never develop dementia.

So it's very important for people who do have dementia, but for those people who don't, we should be extremely careful about it and only, if you were to consider treatment, it would only be treatment in the form of a trial, but as Gare says it, the looking at amyloid in people's brains and seeing about things, about what difference can be made to that by changing your lifestyle is very interesting.

Maybe not very much, because It's not just amyloid, it's how resilient your brain is and quite a lot of these biomarkers are probably more to do with developing a resilient brain or cognitive reserve or not getting vascular damage rather than changing plaques and tangles. 

Geir: Yeah, also remember that this is about Alzheimer's disease.

Still, 40 percent of those who get dementia, they get it from, because of another disease. And when it comes to Parkinson's related dementia, so rebirth of dementia, so frontotemporal lobe dementia, we don't, we are not there yet. But as as the center are really a few ethical challenges around this.

Also, I think even though we can say to a person that you have amyloid or Alzheimer's changes in your brain five years before they start losing the memory, would they want to know it? Yeah. If there is no treatment or disease modifying treatment available, would they really want to know it? 

Gill: Yeah, and that they might not.

There's the other thing. It's not like we can say, because if we could say it'll happen in five years, and the thing to do is take all these trips you've been delaying, do your bucket list, make sure you've got power of attorney and your will sorted out, then that would be one thing. But most of them won't develop dementia, and that makes it, Much more problematic.

Jessamy: And is there a world in which we try and navigate some of these ethical issues, but actually, this risk factor aspect becomes therefore much more relevant if you're saying, obviously this probably wouldn't, it wouldn't meet a screening criteria in terms of, the kind of risk benefit and the cost effectiveness, but where.

People are monitoring some of these things and modifying their lifestyle to try and mitigate any increased risk that they may or may not have. 

Gill: Might make a difference. You're telling people to live a healthy life, what doesn't usually have very much effect. So knowing that they might be at more particular risk might have more.

Interestingly, the studies, and there's not many now, seem to indicate that people really don't want to get dementia and saying to them, this makes you more likely to get dementia. Is and this could be changed, seems to make more of a difference. It might help, but like Gare said, lots of people who get dementia don't have Alzheimer's disease, so it's a very imprecise way of looking at it.

Yeah, I think people will have to do the tests and see, do, if you know you've got amyloid in your brain, are you more likely to make these changes? Or are you less likely to cause you despair? And what happens in one of the young onset dementias where people have a gene, they were much more likely to engage in self destructive behavior because they thought I'm not going to live very long.

Why keep my health? And we don't, we never quite know what's going to happen until we try it. 

Geir: I think we have to be aware of how we put this message through because when I come home to my wife after being in media, talking about what you should do and what you should not do, she then said, says to me that, aren't you realizing that you are just creating fear, anxiety?

Maybe increasing depression, and at worst, also more stigma. I have to acknowledge that it could be something true in that, because if you're not able to follow these advices, you might have this feeling of shortcomings, or increasing anxiety, and so on. And in the end, you could say that it's not straight that I got dementia.

I did all the bad things in the way. So I think it's important that you think about how we phrase this message. 

Jessamy: And maybe we could talk a bit about the treatment landscape, which has also changed it's fairly controversial topic, or there, there seems to be within the community, a bit of a divide about meaningfulness of some of these disease modifying treatments.

It'd be great to hear your perspective and also how it fits into, the commissions. So I think we 

Gill: should start off by seeing it's fantastic. Eventually, and at last, some of these drugs really seem to be making a difference. And that there is some success and that is huge progress and considerable amount of hope.

However, it's not a huge amount of time. Change, there are lots of side effects and it's quite a burdensome and expensive. The drugs are quite expensive and burdensome, so it's only a first step. You have to have first steps in everything. Our mission message is that we should be very open to everyone who's thinking of taking it up about our lack of knowledge, that the change is only small.

What we don't know, I would love to know, is After 18 months or two years, are the people who've been on the drugs, do they do much better? And keep going on and decide is there more of a distance between the two drugs and we really don't know. But I think that this slope of what happens after the first year when it looks like the lines are pretty much falling in parallel might suggest it doesn't modify all that much of the disease.

But if it does, it's a real game changer if things go on and we don't know. 

Jessamy: Because we had decades, didn't we, where actually pharmaceutical companies pulled funding from this area, they weren't willing to invest in new drugs, and now at least there's some excitement in this area, and presumably funding interest from big pharma companies will follow that, and we need that to be able to develop new medications.

Gill: Absolutely. And, instead of thinking it's an impossible problem, it's just a difficult problem. If a drug really made a big difference, then obviously from pharma's point of view, not only would it be good for society, but it would be good for the pharma company. 

Geir: But I'm sure that this is the most controversial part of the commission.

It was in the discussions in the commission, and it will be because a lot of people say, why are you so boring, so negative in a way, but I think on this topic, I think the commission is really balanced and expectant, but there might be other research being published even during the conference, which in a way changes.

This picture, so this is really a field in development. The other thing I'm a bit afraid about is that this focus on monoclonal antibodies removes the focus from other possible agents like tau protein and so on. So I hope in the future that we will be able to use the, what we now learn about monoclonal antibodies.

in association with other possible ways of treating dementia. 

Jessamy: We don't want to become tunnel visioned over one particular intervention. We need the whole spectrum of advances. We do, but 

Gill: the proof of concept, if one thing can make a difference, and it's made a difference in more than one trial, things might be able to make a difference.

Even in people with pure Alzheimer's, and that's relatively rare, lots of people have other things, there's more than amyloid plaques there's it needs to be wider and what we know, we've put, we've tried to be honest, we've tried to balance everything within the commission and explain exactly what we know, but what we know next week, or next year, or in five years might be really quite, it's different like Gator said, it's very different from four years ago, what we know.

Gavin: I wanted to ask actually, because we've been talking about treatments and diagnosis, improved diagnosis, but what actually is the current global landscape of dementia, especially thinking about kind of trends over the last four years what does dementia currently look like in low and middle income countries, for example?

Gill: There's more and more of it around. I suppose it's the big news that I think people think it's a high income country problem 60 percent the people with dementia at the moment are living in low and middle income countries It's expected to be two thirds quite soon. It's a huge problem for in these countries It's a problem which few countries I've thought about, I've had the resources and the tradition to think about in great detail, although more and more of them are.

So I think that's really important. And this is not just rich white people. It's poor people that have more of the problem both within high income countries and out with high income countries. It's an illness which happens more to people who have less.

Geir: And I think one of the changes comparing with the previous commissions is that People representing low and middle income countries and having knowledge about research in these countries and also the clinical reality Are better represented in the commission so in a way you might say that the commission is more diverse in terms of Ethnical background in terms of interdisciplinary experts and so on, which I think is a huge progress and important for the United Commission.

When we discussed this, things that seemed evident, as you remember, we said that the colonist race inhabitants, they are affordable, they're easily accessible. And then somebody told us, no, they're not affordable. They're not easily accessible in many low and middle income countries. So it's been a huge advantage to have these people directing, in a way, the output from it.

Gill: And going back to stigma, dementia still has stigma throughout the world, but that is often more so in low and middle income countries, in particular countries where either for some countries, it's huge stigma. And in other places, many people think they still think that in high income countries, but even more so that it's a sort of inevitable thing that happens when you age and everybody develops dementia but they don't, most people don't.

don't develop dementia. And dementia is an illness and and it's not an illness to be ashamed of. It's an illness and any more than you would be, then you're ashamed of developing diabetes or cancer. It's one of the things that happens to people and more of it happens the older you are. 

Gavin: Over the next few years, I think Jill earlier, you said that it was basically impossible to predict what might go into the next commission update.

If you were going to make a prediction what might you go for? 

Gill: I'm hoping and predicting there will be more in, better drugs. And I'm hoping and predicting that governments around the world will be doing a lot more to prevent dementia. They will look at the economics as well as the social impact of preventing dementia and see that it's a no brainer.

One of my friends called it the dementia bonus. If you, if we do these things and many fewer people have dementia, given that It, and we have a compaction of morbidity, which is, we didn't know about before, but what happens is that even when people develop it they develop it later and live fewer years with it.

So they live till they're older, but for fewer years with having dementia, that saves an enormous amount of money and enormous amount of social stress. So my prediction is in four years time many governments will be taking, will be working on this and trying to prevent as many people as having dementia as possible so that they can have, spend less on illness and have a more of an older workforce.

It's, it makes economic as well as social sense. 

Geir: I hope, as you, but I'm not sure that politicians will think that way. It's not easy for a politician to advocate for prevention strategies. Which only pays off in 20 or 30 years time in a way. So I think this has to become top down in a way also it's important that the World Health Organization keep up, keeps up the pressure, I think, about prevention strategies.

And I also hope for the future that we are. We'll have an even greater emphasis on initiatives to improve lives, people who have dementia today, because no matter how much progress is made in prevention or treatment, there will still in the future be more people who have dementia. Much or most of the research is now on prevention, on diagnosis.

And on treatment, but really also need very good research on how to improve quality of life for those people who have dementia and their caregivers. 

Gavin: That's great. Jill, thank you both so much for joining us on the podcast. It's been a really fascinating and insightful chat and we really appreciate your time.

Jessamy: Okay. Thank you for inviting us. It's been a pleasure to chat. Yeah, thanks. It's been a lovely conversation. Really great to have your perspectives on this.

Gavin: Thanks so much for listening to this episode of The Lancet Voice, and remember, you can subscribe to The Lancet Voice wherever you usually get your podcasts. We'll see you again back here next time.