Simon Lovestone, Professor of Translational Neuroscience, Department of Psychiatry, University of Oxford;
Theme lead for Informatics and Digital Health at the NIHR Oxford Health Biomedical Research Centre
Every morning I see a candidate for prevention of Alzheimer’s disease. He wakes, washes, gets dressed, has breakfast and goes to work. He’s fine; for now. He is a candidate for prevention for only one reason – he is in his mid 50’s.
Alzheimer’s disease creeps up on us so slowly that the amazing capacity of the brain to adapt means we literally do not notice. Research has shown that this period – when the process of Alzheimer’s pathology has started in the brain but there is no apparent effect on the person – lasts for 10, maybe even 20 years. We call this the preclinical period. Given that Alzheimer’s disease becomes common after people reach their mid 70’s, then the man in his 50’s who I live with may just be beginning to have the very first changes in his brain, even if he doesn’t know it.
This very long preclinical period is both an enormous problem and, potentially at least, an astonishing opportunity. The problem is that by the time dementia sets in, the disease has been present for such a long time that it may be too late for most drugs to work. The flip side is that if we could intervene in this preclinical stage, then we might have a chance of slowing down dementia or even reducing the chances of it affecting the person at all. Such intervention is called secondary prevention, to distinguish it from prevention to stop the disease process starting at all.
The trouble with secondary prevention studies
So some questions then – how will we identify people with signs of preclinical disease, and what will we use to prevent them from developing Alzheimer’s? Just how hard is it going to be to do secondary prevention studies?
Take the man I live with as an example – could he enter a study for a secondary prevention intervention? We would need a way to see if he has the very early signs of disease in his brain. In fact, we have neuroimaging scans that can measure the amount of amyloid and tau proteins in the brain; both features of Alzheimer’s. We can also measure these proteins in the fluid that bathes the brain – cerebrospinal fluid (CSF). These tests are however time consuming, uncomfortable and expensive, and relatively few people who take the test turn out to have preclinical dementia.
Not only that, but if someone enters such a trial, how do we know if the secondary prevention intervention has worked? We cannot measure symptoms because the person doesn’t have any. So all we can do is wait to see if the person develops dementia. And because the preclinical period can last 10 years or more, that can be a very long time.
Identifying preclinical dementia
My own research has focused on trying to overcome these two problems.
To identify people who might be in the very early stages of preclinical disease, we have, in the past five years, examined the blood of more than a thousand research volunteers for proteins that are altered when the brain shows some signs of preclinical disease. Excitingly we have found such proteins and developed a way to test for them.
We have a lot of work to do yet – we need to turn our complicated test into something simpler and more stable, we need to replicate again and again, and we need to work out exactly how accurate a predictor the test is. But the progress has increased in pace, and it’s just possible we could be using protein blood tests as part of clinical trials for prevention in the next year or two.
Measuring whether secondary prevention works
The second problem we are now tackling is the tricky one of how to find out whether a preventative intervention is working if there are no symptoms to measure. We wondered if there might be some subtle sign in the way the brain works that we could measure instead.
In the Deep and Frequent Phenotyping study, funded by MRC and NIHR, we are going to do neuroimaging and CSF tests, but then also measure brain structure with MRI and brain function with functional imaging and electrophysiology. Not only that, we will measure everything we can in blood and urine and look in detail at the retina. We will also use devices, including smartphones, to measure memory, behavior, gait and more. We will measure all these things repeatedly over a year, so we will be able to see what changes in people who develop preclinical disease.
Accelerating secondary prevention studies
With these two approaches, we hope to make it possible to do secondary prevention trials quicker and more effectively. With our blood test, we hope to be able to identify people who are more likely to have preclinical disease. And with the Deep and Frequent Phenotyping study, we hope to find a test that would be able to say whether a secondary prevention intervention was having an effect or not.
Which of course begs the question – what interventions could we use for secondary prevention? Here scientists are not short of ideas. Exercise and other behavioural interventions might be useful, and a growing number of drugs are being developed that might work for secondary prevention. But we need to do more trials, of more approaches. We need to start them quicker and run them more effectively.
The need for secondary prevention of Alzheimer’s disease is urgent: for all those people now in their 40’s and 50’s, as well as for older people. It’s urgent for the man I live with. If you haven’t guessed already, that man I live with is me. If you want to know who is a candidate for secondary prevention, then look at me. Perhaps look in the mirror too.
Blog kindly republished from the NIHR blog.
*Professor Sir Simon Lovestone is Professor of Translational Neuroscience in the Department of Psychiatry at the University of Oxford. He is Head of the Informatics and Digital Health research theme at the NIHR Oxford Health Biomedical Research Centre and is an Emeritus NIHR Senior Investigator. He was previously Director of the NIHR Dementia Translational Research Collaboration.
**NIHR is running a campaign to mark World Alzheimer’s Month. Find out more on the NIHR website.