Has Alzheimer's treatment hit a turning point?

Is our understanding of the disease leading to a shift in treatment?
26 March 2024

Interview with 

Will McEwan, Cambridge University’s UK Dementia Research Institute




The scans aiming to detact early signs of Alzheimer's disease look for amyloid and tau protein aggregates in the brain. But can we be sure that these proteins are the cause of the disease? William McEwan is a group leader at Cambridge University’s UK Dementia Research Institute…

Will - The best evidence is that people who have rare genetic forms of these diseases can have mutations in the genes that encode these aggregating proteins. So there's familial forms of Alzheimer's disease where there's mutations in the gene that encodes beta amyloid and these people develop early onset forms of Alzheimer's disease. And similarly for tau, people who have mutations in tau have familial forms of what we call tauopathies. They're not Alzheimer's disease because they don't also have the beta amyloid pathologies. But these observations were critical in really linking these protein pathologies to cognitive effects that we see.

Chris - And how do you think then, if we do believe, and that's pretty compelling evidence, isn't it, that they cause Alzheimer's disease. How do you think those proteins do that?

Will - The best framework that we have in Alzheimer's disease is that beta amyloid is a kind of trigger. So once that starts aggregating, it causes, and we don't really know how, it unleashes a cascade of events that ends up in neurodegeneration and tau pathology. So we don't really understand that, we think, from human genetics. So when we look at people who have Alzheimer's disease versus those who don't, we can pick up what are called genome wide association studies. So these are looking at across the genome, what are the genetic signatures behind Alzheimer's disease. It comes up with genes that are involved in inflammation. So we think that the immune system might have something to do with it and other cellular processes involved in handling fats in cells.

Chris - So that would argue then, and hence that explains why scientists believe that if we go after these proteins that are building up and we find a way to either stop them building up or dismantle these clumps, we have a chance of getting ahead of what is causing inflammation and therefore causing the disease to progress.

Will - That's exactly right. And the earlier we go, the better it's going to be.

Chris - And how are people trying to do that?

Will - The main approach at the moment, and it's recently been in the headlines, is using antibodies. So antibodies are molecules that your body makes to fight infections normally, but they're very good at sticking to things. So we can re-engineer them to stick to essentially whatever we like. People have re-engineered them to stick to beta amyloid and once they start sticking to the beta amyloid, your immune system then starts seeing that beta amyloid is a threat. So it starts then degrading it and clearing it. So these antibodies are delivered to people by an intravenous route and they make their way into the brain, they stick to the beta amyloid plaques and start causing their clearance. And over a few weeks of being treated with these antibodies, you can see in the brain scans that the amount of amyloid in their brain is substantially reduced.

Chris - That did appear also to map onto a clinical benefit, didn't it? Because of the people who got those infusions, it was reported that the disease slowed down in terms of how much worse the people were getting by about 30%. But you could say it was only 30%. Why do you think it was only 30%?

Will - That's a really good question and to be honest, we don't know the exact answer. It could be that it's too late. I mean, I think the main hypothesis is that when these people were treated, they already had symptoms and this beta amyloid cascade, if you will, had already been unleashed. So all we were doing was buying people a bit more time. So again, putting this emphasis on trying to diagnose people as early as possible so that we can intervene hopefully with a view that you might be able to extend that benefit.

Chris - What about side effects? Because there were some people who got quite dramatic as in the lethal side effects of doing this. Do we know why that happened and what we might be able to do to mitigate that?

Will - Yeah, so I think this is an inherent risk of antibodies. So antibodies have, they stimulate the immune system. That's what they're designed to do. In doing so, there is an inherent risk that they will overstimulate the immune system. Now, having shown that clearing beta amyloid is beneficial, if we can do this in another way that is not so aggressive, is not so stimulatory to the immune system, the path has been cleared to a new generation of drugs.

Chris - All of the emphasis so far though seems to have dwelled around beta amyloid. And you've mentioned it does have a partner in crime, tau. So are people going after other things other than just beta amyloid as well? And could it be that in fact the ideal therapy for Alzheimer's disease is going to focus on not just one thing but a whole raft of different targets. We give a sort of cocktail of treatments that hit the disease from a range of different directions.

Will - I mean my background is in virology actually. And that's been a very powerful approach certainly for viruses like HIV and also in cancer. So I think we can learn a lot from those fields. And my own research is looking at clearing tau. So tau occurs not only in Alzheimer's disease but also rarer dementias and neurodegenerative diseases. And actually, the amount of tau pathology that you have correlates much more closely with the amount of neurodegeneration suggesting it's much more closely related to the toxic effects of the pathological progression of Alzheimer's disease. So I think you are absolutely right. We do need to be looking at these other targets downstream of beta amyloid.

Chris - On the other hand though, it's only been in the last year or so that I think I've really had reason to be optimistic about this disease previously. I think we were very good at telling people they had it. We were very good at telling people why they were having problems. We were not very good at doing anything about it. And it seems we are on the verge of turning a corner.

Will - Yes, I think you're right. I think this really gives us hope. These are not the ideal drugs. These are not the drugs that will be prescribed in 20 or 30 years, but they will be the turning point. They'll be seen as the moment where we know that this is ultimately a treatable disease.


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