Dr David Reynolds
Chief Scientific Officer at Alzheimer’s Research UK
Alzheimer’s Research UK is the UK’s leading dementia research charity and is dedicated to funding pioneering research to find ways to understand, diagnose, reduce risk and treat dementia.
Since Alois Alzheimer first described amyloid plaques in the brain of Auguste Deter in 1906, Alzheimer’s disease has been known to the world.
Over a century later, we are still waiting for the first disease-modifying treatment. With drugs designed to target the disease processes driving Alzheimer’s having so far failed to show ultimate success in clinical trials, have we learnt anything about how to treat this cruel disease?
In short, yes, we have. In fact, we’ve learnt an awful lot.
It’s taken many years to do so, but research has shown that Alzheimer’s is a physical disease and not a natural part of ageing. We now know more than ever about the genes, molecules and proteins involved in causing the disease and that is helping us zero in on the most promising areas of research to improve the lives of those affected.
Alzheimer’s disease currently accounts for two-thirds of all dementia cases, that’s around 500,000 people in the UK alone living with the disease. So, how close are we to turning this understanding into new treatments?
Research made a huge leap forward when scientists discovered the amyloid precursor protein gene. This gene is faulty in some rare families and goes on to cause early-onset Alzheimer’s disease. This genetic discovery pointed towards the build-up of a protein called amyloid as the key event that kick-starts damage to nerve cells in Alzheimer’s. This idea is known as the ‘amyloid cascade hypothesis’ – a theory that has been central to Alzheimer’s research for nearly three decades.
The improperly processed amyloid protein clumps together to form sticky plaques in the spaces between nerve cells in the brain, ultimately causing these cells to die. This loss of nerve cells means the brain can’t function properly and people start to experience symptoms, like memory loss, confusion and changes in mood and behaviour.
Anti-amyloid treatments are perhaps the most immediate drugs on the horizon and I am hopeful of success stories here, but there have been a number of high-profile set-backs in recent clinical trials that we must learn from. Alzheimer’s is a complex disease and to have the best chance of success, researchers must continue to tackle the problem from as many different angles as possible.
Research is now also highlighting other key brain changes that occur in Alzheimer’s disease, opening the door to new targets for potential treatments.
The build-up of the tau protein is a feature of a number of different degenerative brain diseases and is also characteristic of Alzheimer’s disease. The tau protein, which normally helps nerve cells maintain their proper shape as well as transporting cargo around cells, becomes modified during Alzheimer’s disease. One type of modification is the addition of a specific molecule, called phosphate, to particular parts of the tau protein. This changes the shape of the tau protein and can trigger an abnormal build-up into tau tangles. Drugs that could prevent tau from being modified or even clear away tangles of protein in the brain are a key goal for drug discovery scientists.
The abnormal build-up of proteins is a key hallmark of many of the diseases that cause dementia, and processes that control protein synthesis and degradation are now an important area of research focus. Understanding how we could target these larger scale processes will help to identify drugs that could benefit several diseases rather than focusing specifically on a single protein associated with a single neurodegenerative disease.
Another relatively recent, but key focus of work is the role of the immune system in the development of Alzheimer’s disease. We now appreciate that the brain has its own immune cells – microglia – which play a more important role in the disease processes than was once thought.
We know from other areas of health research that the immune system provides the body with a beneficial defence mechanism, but in Alzheimer’s, research suggests that overactivity of the immune system could exacerbate the disease. Unpicking which parts of the immune system have an influence, at which points in the disease and in which patients, is a key area of research and offers a great opportunity in this space for potential treatments. When we understand the contribution of the immune system to Alzheimer’s more fully, we may be able to find shortcuts to new medicines for dementia by repurposing some of the many drugs that already target the immune system for disorders in other parts of the body.
Although Alzheimer’s disease can start in specific susceptible brain regions, this damage spreads as the condition progresses, causing more widespread and diverse symptoms. In fact, the brain of a person affected by late-stage Alzheimer’s is about 140 grams lighter than an unaffected brain – that’s about the weight of an orange.
We also now know that this damage, and the build-up of proteins in the brain, can start ten to fifteen years before symptoms start to manifest. So, it may well be that we have already discovered a drug or drugs that could help slow or stop the progression of Alzheimer’s, but we just haven’t been able to test them early enough.
Diagnosing people early with diseases like Alzheimer’s will be vital as we work to refine how we test emerging new treatments. A multifaceted approach is needed to do this as Alzheimer’s is a multifaceted disease. Focussing on one single detection technique is unlikely to provide all the information doctors will need to make a diagnosis. Combining genetic information, blood tests, brain scans, information we can glean from spinal fluid, as well as subtle changes in brain function using a battery of cognitive tests may give us the best chance of identifying those in the very earliest stages of Alzheimer’s who could benefit from future treatments.
We’re also seeing some really innovative approaches being developed to address the challenge of early diagnosis in diseases like Alzheimer’s, including exploring how data can be collected from apps, wearables and smart devices to give a more holistic view of someone’s physical, cognitive and social activity and how it’s changing over time.
All of this important research requires funding, and thankfully the research landscape is beginning to change for the positive. We’re seeing a more joined-up approach of industry, academia and charity and this is reflected in our funding strategy as a charity. At Alzheimer’s Research UK we have established some cutting-edge drug discovery initiatives like our Drug Discovery Alliance and Dementia Consortium that are fast-tracking the translation of promising lab discoveries towards new drug molecules. Drug discovery is not a quick and easy process but having a broad pipeline of approaches gives us the greatest chance of success for people affected by dementia.
We are also now investing heavily in a world-leading research institute to revolutionise discovery science in dementia. This is the UK Dementia Research Institute (UK DRI), a £290million initiative founded with funding from the Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. The six centres of the UK DRI are now up and running more than 700 scientists expected to take up roles in the institute as its suite of research projects begin to get underway.
This is a game-changing initiative. The UK DRI is not just bricks and mortar, it’s a network of experts across the country sharing knowledge, skill and ideas to change lives sooner. However, although the UK DRI is an important step forward and a strong foundation for further investment, we need to make sure dementia research doesn’t fall off the political radar. The job is by no means done and I hope the government sees this as a starting point for even more ambitious change for people with dementia and their families in future.
It is through the dedication and hard work of researchers that we will continue to drive breakthroughs that pave the way for new treatments and provide hope to people with dementia and their families. I am hopeful for the future, new treatment approaches are coming through into clinical trials and at an increasing rate. The research landscape has changed considerably, but of course there is still much work to do.