How Britain plans to lead the global science race to treat dementia


It has struck nearly a million people in the UK, yet even its cause is still unclear

CT scans of a brain showing the progress of Alzheimer’s disease. Atrophy is shown by enlarged ventricles (white areas at the centre).
CT scans of a brain showing the progress of Alzheimer’s disease. Atrophy is shown by enlarged ventricles (white areas at the centre). 

Early next year, Professor Bart De Strooper will sit down in an empty office in University College London and start to plan a project that aims to revolutionise our understanding and treatment of dementia. Dozens of leading researchers will be appointed to his £250m project which has been set up to create a national network of dementia research centres – with UCL at its hub.

The establishment of the UK Dementia Research Institute – which was announced last week – follows the pledge, made in 2012 by former prime minister David Cameron, to tackle the disease at a national level and comes as evidence points to its increasing impact on the nation. Earlier this year, it was disclosed that dementia is now the leading cause of death in England and Wales. At the same time, pharmaceutical companies have reported poor results from trials of drugs designed to slow down the progress of Alzheimer’s disease, the most common form of dementia.

“Humans have truly wonderful brains that can cope with terrible diseases like Alzheimer’s for decades and can find all sorts of ways to get around defects that are growing inside,” said De Strooper, who is currently based at the University of Leuven in Belgium. “Eventually individuals succumb to the condition and start to display memory loss and other symptoms – but usually only after decades have passed and their brains have gone through considerable changes. This makes it very difficult to treat the disease. That is the challenge that we need to tackle.”

Current understanding of Alzheimer’s suggests the disease is triggered when beta amyloid, a protein in nerve cell membranes, starts to clump together. Slowly the brain undergoes metabolic changes as amyloid clumping continues. In particular, a protein known as tau, which is involved in memory storage, is affected. It starts to form tangles inside the brain’s neurons and these die off. Eventually, symptoms – such as severe memory loss – manifest themselves.

To date, most attempts at drug interventions have focused on medicines that could prevent beta amyloid from forming clumps, the most recent being Solanezumab, developed by the pharmaceutical company Eli Lilly. However, results of clinical trials of the drug – revealed last month – indicated that it had no significant effect on the thinking abilities of people with mild Alzheimer’s. Solanezumab had also failed in people with more advanced versions of the disease in earlier trials.

This double failure has led some scientists to argue that amyloid clumping is not a cause of the disease but is merely a symptom. By targeting it, scientists are wasting time, it is argued. Professor John Hardy, a geneticist based at UCL – who has played a key role in setting up the college’s Dementia Research Institute – does not agree. “All the evidence we have from families affected by early onset dementia indicates that the disease begins with the deposition of amyloid plaques in the brain,” he said. “The trouble is that this buildup starts 15 to 20 years before dementia’s symptoms appear. The drugs we have developed so far offer treatments that are, in effect, too little and too late.”

Hardy drew a parallel between cholesterol buildup in blood vessels that eventually leads to cardiac disease and the buildup of amyloid plaques in the brain and the onset of Alzheimer’s. “Unfortunately, we have no equivalent of a cholesterol test to assess how much amyloid is clumping in a person’s brain,” he added. “However, that could change in the near future.”

Research suggests between 20 and 30 genes are involved in predisposing people to Alzheimer’s.
Research suggests between 20 and 30 genes are involved in predisposing people to Alzheimer’s. 

Recent research has pinpointed a group of around 20 to 30 genes that are involved in predisposing individuals to Alzheimer’s. These genes come in different variants. Some variants of a gene predispose individuals to dementia more than other variants of that gene. If a person inherits a package of genes made up of variants that particularly predispose to dementia, they are very likely to develop Alzheimer’s.

“We are now within five years of developing a chip that will be able to tell – from a blood test – whether a person is likely to have amyloid plaques forming inside their brains in middle age,” added Hardy. “This would then be followed up by a brain scan to confirm if this is true or not.”

This would be dementia’s equivalent of a cholesterol test. The problem is that there is, as yet, no equivalent of drugs which would halt this amyloid buildup in a way that parallels the use of statins to block buildups of cholesterol, once detected, and so head off cardiac illness. For their part, researchers argue that the use of drugs like Solanezumab – although seemingly ineffective on patients in whom amyloid plaques have become established – could be far more effective in the early stage of the condition.

Many other issues complicate our understanding of dementia, however. “A good example is provided by the immune system,” said David Reynolds, chief scientific officer of Alzheimer’s Research UK. “There is a lot of evidence now that the immune system is involved in the development of Alzheimer’s after beta amyloid clumps appear.”

However, the nature of that immune response is still not fully understood. “We do not know whether the immune system tends to overreact – as with conditions like rheumatoid arthritis in which the body’s own tissue is attacked by its own immune defences – or react weakly and allow amyloid clumps to develop when they could be stopped,” added Reynolds. “Certainly it would be unwise to wade in with drugs until we know exactly what it is we want to achieve.”

And this is where the distributed nature of the Dementia Research Institute network could prove important. Based in different university cities (Edinburgh, Oxford and Cambridge are all candidates for units), these outlying centres will focus on different aspects of the disease: environmental factors, care of dementia patients – and immunology. “The creation and direction of these centres will depend on existing expertise at that university,” added Reynolds. “A centre that focuses on immunology and dementia would be particularly useful in finding new ways to tackle the condition.”

The Dementia Research Institute network is to be supported, over the next 10 years, by £150m funding from the Medical Research Council – with further inputs of £50m each being made by Alzheimer’s Research UK and by the Alzheimer’s Society. This commitment marks a significant increase in dementia research in the UK, which had already raised its annual funding from £50m in 2008 to £90m in 2012 and is now a world leader in the field.

“It is good news but we need to put it in perspective,” said James Pickett, of the Alzheimer’s Society. “In 2012 we spent more than £500m on cancer research; there are five times more researchers working on cancer in the UK; while the number of clinical trials of dementia drugs is less than 1% of those of cancer drugs.”

At the same time, the need for some form of treatment to tackle dementia is becoming increasingly urgent. More and more people are living to their 80s and 90s when their chances of getting dementia increase markedly. There are currently 850,000 people with dementia in the UK, a figure that will rise to one million by 2025 and two million by 2051.

“We are going to have to be very nuanced in understanding all the risk factors involved in dementia – and in appreciating why factors like education and general health provide some protection against its onset,” said Professor Carol Brayne, of Cambridge. “That is going to be the strength of the institute. It offers us the opportunity, for the first time, to follow so many different avenues and approaches to dealing with and understanding the dementia.”

GROWING THREAT

Dementia overtook heart disease as the leading cause of death in England and Wales last year. More than 61,000 people died of the condition in 2015, 11.6% of all recorded deaths.

The Office for National Statistics said the increase had occurred because people were living for longer while deaths from other causes, including heart disease, had gone down. In addition, doctors are now better at diagnosing dementia, and it is appearing more often on death certificates.

The bulk of dementia deaths last year were among women: 41,283, compared to 20,403 in men.

According to the Alzheimer’s Society, dementia is the only one of the top 10 causes of death that we cannot prevent or even slow down.

The leading cause of dementia is Alzheimer’s disease, which accounts for 62% of all cases in the UK: 520,000 of the 850,000 people living with dementia in the UK today. Other forms of the disease include vascular dementia and Lewy Body dementia.

Dementia costs the UK economy approximately £26bn per year, according to the Alzheimer’s Society.

If a drug could be found to slow cognitive decline in dementia, that would delay the need for paid care and reduce the financial burden on families, the NHS and social care.

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