Why Alzheimer's drugs keep failing

16 September 2016

Interview with

Professor Simon Lovestone and Jennifer Lawson, University of Oxford

If we know tau tangles and amyloid plaques are the cause of Alzheimer's, why An assortment of drugscan't we just blitz them? Kat Arney put this to Simon Lovestone...

Simon - We now know how the amyloid that forms the plaque gets formed and there have been drugs designed to prevent that formation or, indeed, to clear that plaque once it's already formed. They've gone through clinical trials; so far none of those clinical trials have worked. I think there's a different reason why they haven't worked; I don't think it's just because the drugs are no good.

Kat - What is that reason? You can't give me that teaser and not tell me.

Simon - The trials are done too late. So one other thing, and this is surprising; we didn't know this until a few years ago but those plaques and tangles start to form ten, perhaps twenty years before there are any clinical symptoms. So this is not doctors not picking up dementia, that's another problem; this is there is no dementia, there are no clinical symptoms and that's probably because the brain is such an amazing organ. It's plastic, it's able to cope with a certain amount of damage without causing symptoms. So there's this long period, up to twenty years, where the disease is happening but there are not symptoms. Now the trials, they're done in people with dementia. I think, and I think the majority of the world thinks, those trials are done way too late. It's too much to ask these particular drugs to have a substantive effect after twenty years of disease.

Kat - What we need to do then, is spot the disease earlier. But that's not easy, especially since people don't have symptoms until very late on. However, Simon and his colleague Jennifer Lawson have won a huge Medical Research Council grant for a clinical trial that they hope will change that by finding biomarkers. Much like a blood test can reveal a high levels of antibodies, and therefore whether you have an infection, Simon and Jennifer hope to find some similar marker for Alzheimer's. Here's Jennifer...

Jennifer - We're going to take about two hundred and fifty volunteers and ask them to take part in the study. These are people who might have a range of health profiles; some people might appear be more at risk of getting Alzheimer's disease than others and what we want to do is track the really early changes that happen in the human body before we see memory changes.

Kat - So these are people who don't have Alzheimer's and also you don't know that they're going to get Alzheimer's?

Jennifer - That's right. We don't know if they're going to get Alzheimer's. At the moment, we know there are various genetic factors that make somebody more at risk of getting Alzheimer's. But we know that's not the whole picture and we urgently need to find other ways of tracking Alzheimer's well before people end up with memory problems so that we can target treatments at people, at that stage, and we can run clinical trials in that population as well. And that's the stage at which we think it's most likely to make a difference to people's lives.

Kat - So with this study you've got these two hundred and fifty people. What are you doing with them - how are you studying them to try and find these markers that may show that they are or aren't going to develop the disease?

Jennifer - We are going to use every test we can think of that might show us something valuable in this population. So we will do a whole host of tests; they'll be about fifty tests on people over a twelve month period, so it's quite intensive. We're going to do MRI scans, there'll be MEG scans, and PET scans, so three different types of brain imaging in the same population in the same volunteers.

Kat - That's a lot of brain scanning!

Jennifer - That's a lot of brain scanning - yes. And there'll be blood tests, there'll be cognitive tests alongside which tests people's memory, reasoning, and thinking skills. We'll also do eye tests looking at the retina at the back of the eye; we think we might be able to detect some changes in the morphology of the blood vessels at the back of the eye there and possibly pick up some early degeneration well before you see any other changes. We're also looking at wearable technologies, so there's lots of things to look at people's gait and movement. Really subtle things that you wouldn't pick up yourself with your fitbit; these are like more highly specialised pieces of equipment that are being used to detect really subtle changes, so that needs to be analysed by some proper science in a lab.

Kat - So say you come up with this profile; this sort of set of measurements that you can say okay, this person is getting worse or this person is getting better. What happens next?

Jennifer - Once we have a set of biomarkers that we're quite confident will show us how someone is progressing with Alzheimer's disease, we can then start to trial Alzheimer's drugs in a more effective way. In recent years, ninety-nine per cent of clinical trials in treatments of Alzheimer's disease have failed. It might be that many of those drugs actually would be effective if only we could target people at the right time. So we might be able to retest some of those compounds that previously haven't worked or we might be able to generate new compounds at the areas we have picked up from this trial.

Kat - If we can pick up the disease much earlier on, then, could we also screen for it? I put this to Simon Lovestone as my grandmother had Alzheimer's and I was keen to know if I, or my parents could be tested...

Simon - The short answer to that is no. And I'm not sure that we'd want something either. Right now we don't have any drugs for dementia and really you don't really want to screen until you've got something you can do if you find out you're screened positive.  We are though trying to work on tests or biomarkers for dementia and the reason why we aren't though is not to screen populations but to help in the diagnostic process.

So when an older person comes to the GP and says they've got memory problems right now, it's almost impossible to tell whether that is just the memory problems that happens as people get to be elderly, or whether it's the start of the dementia process. So we really like tests to help that clinical practice but, even more than that, we need biomarkers or tests to help do clinical trials earlier in the disease process more effectively. That's what we really want to test for, not for screening.

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