Early signs: Finding changes in mid-life linked to Alzheimer's

From Care and cure magazine - Summer 2016, find out more about early signs of dementia and research into them.

It is often said that prevention is better than cure, and it is crucial that we better understand what factors might affect our risk of developing dementia later in life. The PREVENT study is studying hundreds of middle-aged people to find out what might be at work.

'What’s my risk of getting dementia and what can I do about it?'

When asked this question by a middle-aged patient with a strong family history of dementia at his cognitive disorders clinic, Professor Craig Ritchie replied, 'I don't know and I don't know. We don't know for people like you in your 50s what your risk is and what works for you.'  

When the patient responded, 'Well, you’re going to have to do something about that,' it prompted Professor Ritchie to set up the PREVENT study to answer these questions.

PREVENT is unusual for a dementia research project as it is studying people in their 40s and 50s, long before you would expect to see symptoms of dementia. However, this is crucial to understand what changes happen in the body at the very earliest stages of the condition. 

Subtle changes

In recent years we have started to understand how long it can take for diseases likeAlzheimer's to develop. Previous research found subtle differences in memory tests up to 18 years before dementia is diagnosed. While the differences are far too small to be able to reliably identify who is at risk, we can see the effect when results from hundreds of people are studied together.

What this suggests is that if we want to prevent dementia then we need to act in mid-life, at the very earliest stages of the disease. The problem is that we do not know what these early stages actually look like, as by the time someone has a diagnosis it could be years later.

Finding these subtle, early changes is like looking for a needle in a haystack. Professor Ritchie is keen to make sure that they do not miss anything, so each person in the study is examined for their memory, genetics, lifestyle, diet, physical and mental health. They also have brain scans and give samples of blood, saliva, urine and spinal fluid. 

'There have been other studies looking at this age group but they haven't gone into this much detail,' he says.

While most studies have to spend a lot of effort recruiting suitable people to take part, there has been so much demand to sign up to PREVENT that the researchers have had to open a waiting list. The study began at Imperial College London in 2013 with funding from Alzheimer's Society. The study has since opened in Edinburgh and the Society is funding a further two recruitment sites in Oxford and Cambridge that will open this summer.

What we know about risk factors for dementia has come from studies that have either followed a group of people for a long time or looked at health records for a population. One example is the Caerphilly study, which monitored a group of 2,500 men from the Welsh town since 1979 and found that those who had healthier lifestyles were less likely to develop dementia.

From studies like this, we have evidence that eating a healthy (in particularMediterranean-style) diet, being physically active and not smoking are linked to having a lower risk of dementia. However, we cannot know this for sure without comparing one group who, for example, change diet to a similar group who keep the same lifestyle habits.

'There are a lot of things that we propose may be helpful, but there's nothing that we absolutely know. In this age group there's lots of speculation that lifestyle factors are important in reducing your risk, but until we actually do specific trials I think it's going to be very hard to prove that,' says Professor Ritchie.

Biomarkers

The problem with these kinds of trials is deciding what to measure to know whether you are seeing a real difference. The development of dementia is an obvious choice, but if you are studying middle-aged people then the trial might need to run for 20 or 30 years to see any benefit.

In looking at the samples and scans of its participants, the PREVENT study is hoping to find biological differences or 'biomarkers' between those who are at high risk of dementia and those at low risk. These biomarkers can then be a way to monitor the risk of developing dementia in later life. 

'If you can affect these biomarkers then you have confidence that you're actually changing the course of the illness,' says Professor Ritchie.

'There are parallels with heart disease where you'd intervene in mid-life and look for improvements in cholesterol, blood pressure and coronary artery blood flow, and you take that as an indicator that you've reduced your risk of having a heart attack.'


 'It is kind of the equivalent of having an MOT carried out.'

Hear from Malcolm, one of the participants in the PREVENT trial, in an article in Living with dementia magazine.


Secondary prevention

These biomarkers would be very useful in so-called 'secondary prevention' trials. This is where researchers try to stop or slow the progress of the disease in the brain before the outward symptoms of dementia appear.

The large gap between the development of the disease and the onset of dementia symptoms provides a large window of opportunity. Drugs that previously failed in trials with people with mild-to-moderate Alzheimer’s disease might have potential when given even earlier. These drugs are now being tested in people who have inherited genetic mutations that mean they are certain to develop young-onset dementia. 

The ultimate aim for PREVENT would be to one day help inform prevention trials like this for healthy middle-aged people without that genetic certainty. To do this, we would need to understand what signs indicate that someone is at risk of Alzheimer’s and what to measure to check if a drug is helping.

The PREVENT participants have now been well studied before any signs of Alzheimer's disease, making them very useful for taking part in such drug trials. The first of these participants has recently been approached to take part in a study as part of the European Prevention of Alzheimer's Dementia consortium.

While this secondary prevention work will take many years to come to fruition, the PREVENT researchers are already working through the data they have collected and will publish their initial findings later this year. Preliminary results show differences in patterns of brain activity in a memory test for people at higher risk of Alzheimer's. Once further tests, samples and participants are studied we may finally get a clearer picture of what Alzheimer's disease looks like from the very beginning. 

To sign up to the PREVENT project and to other studies, please visitwww.joindementiaresearch.org.uk

To hear from one of the participants in the PREVENT trial, read our article in Living with dementia magazine.

Further reading