Dispatching dementia

Scientists are finally making breakthroughs in the search for a cure.

High in the mountains of Papua New Guinea, deep within a humid rainforest, lives a secretive tribe known as the Fore people. Until the 1950s, this intensely traditional community — numbering around 20,000 — had little contact with the outside world. When anthropologists finally tracked them down, they made a startling discovery: the Fore’s funeral rituals involved gruesome cannibal ceremonies, where women and children ate the brains of the dead and men devoured the flesh.

It may sound the stuff of nightmarish fiction, but this year scientists made an astonishing link between the cannibalistic practices of this tribe and dementia. Experts at University College London found that, while eating the bodies of their deceased tribesmen caused a degenerative neurological condition called ‘kuru’ to spread among the Fore, it also caused a beneficial mutation in their brains. The Fore developed a variant of a human protein called a prion that eventually made them resistant to other prion-related disorders such as Creutzfeldt-Jakob Disease (CJD), a form of dementia.

Cannibalism, in other words, caused this tribe from a remote corner of the globe to acquire something no western scientist has been able to reproduce in a test tube: resistance to a disease that affects 850,000 people in Britain and 47.5 million worldwide. Armed with this discovery, researchers are now one step closer to understanding the causes — and potential treatments — of dementia. It may, they hope, even be the catalyst for a breakthrough.

In an otherwise bleak landscape, this finding represents a glimmer of hope. Dementia is one of the deadliest and most disturbing scourges of the 21st century, variously described by experts as a ‘ticking bomb’, a ‘tsunami’ and a ‘plague’. Over a century has passed since 1906, when psychiatrist Dr Alois Alzheimer gave a lecture in Tubingen, Germany, in which he described a ‘peculiar disease of the cerebral cortex’, the first indication that dementia was an illness and not a symptom of ageing. Today, this illness costs the global economy £408 billion a year and, though palliative drugs and treatments exist, a cure remains elusive.

Why? Medical research has come on in leaps and bounds in combating other potentially fatal conditions in the past 25 years: HIV, cancer, heart disease. Yet dementia remains woefully misunderstood, with the number of cases rising at an alarming rate. The latest statistics from the US-based Alzheimer’s Association predict 100 million worldwide by 2050. Surely eating human brains can’t be the closest experts have come to finding a cure?

The biggest stumbling block comes in understanding the myriad diseases that we know as dementia. It is an umbrella term for around 50 conditions, broadly characterised by memory loss, concentration difficulties, loss of language skills and mood changes. It mainly affects people over 65 (one in 14 people in this group have dementia), and its likelihood increases with age — though, to further complicate things, it is also found in younger people, with 40,000 under 65 in the UK.

The most common form is Alzheimer’s disease, accounting for 60 to 70 per cent of cases, but others include vascular dementia (caused by the narrowing of blood vessels in the brain), dementia with Lewy bodies (to do with disruptive molecules developing in the brain) and frontotemporal dementia (when the front and side parts of the organ are damaged). Getting to grips with each is a highly complex, time-consuming task. ‘You need to be very clear about what dementia is,’ warns Professor June Andrews, a global dementia expert at the University of Stirling. ‘It is a group of symptoms caused by a group of diseases. You can do lots of things about the symptoms without doing much about the disease. Imagine a disease that is so clever, you don’t know you’ve got it until the symptoms have taken hold. It can be caused by a range of problems — blood supply genetics, lifestyle issues, metabolism of brain tissue going wrong, head injury, stress.’

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What scientists do know — or at least think they know — is that, as the disease progresses, deposits known as ‘plaques’ and ‘tangles’ appear and spread in the brain. Plaques are the build-up of sticky, abnormal proteins called beta amyloids, while tangles are twisted strands of a protein called tau. In Alzheimer’s, these disrupt normal brain function, eventually causing the irreversible disintegration of cognitive tissue. But even this is not straightforward.

‘The predominant theory is that it is caused by the accumulation of beta amyloid plaques, which are believed to have toxic effects in the brain,’ explains Dr Matthew Kan, of Duke University in the US, whose tests on immune cells successfully managed to halt dementia in mice brains this year. ‘However, beta amyloids’ true biological role in the disease is poorly understood. There may be other unknown factors that play a more direct role.’

What’s more, the physiology of the disease makes it almost impossible to pick apart. ‘The brain is encased in bone in the skull, so, unlike other parts of the body that you can see and access, looking into somebody’s brain is really difficult,’ says Frank Gunn-Moore, professor of molecular neurobiology at the University of St Andrews. ‘When you do finally get to look inside, during a post-mortem examination, it can be 20 or 30 years down the line from when the disease first hit. And dementia makes the brain shrink. As it physically disappears, there’s very little left to dissect.’ Crucially, there are no biomarkers for dementia — no simple blood or urine test or brain scan for early sufferers, or indeed potential sufferers, to confirm its existence. ‘A lot of people have the underlying disease for ages and never get the symptoms,’ explains Andrews. ‘Some have the underlying disease, but the symptoms are undetectable because they have simple, easy lives — you wouldn’t know they had it. Others get the disease and the symptoms hand in hand.’ Scientists are desperately seeking answers, including whether there may be a genetic link.

Treatment options are limited to controlling and, in some cases, halting the progression of symptoms. The main group of medications are cholinesterase inhibitors, which slow the breakdown of a vital neurotransmitter called acetylcholine, and these include donepezil (brand name Aricept), rivastigmine (Exelon) and galantamine (Reminyl). Their aim is to relieve memory problems and improve alertness, but effects vary. Those with more severe symptoms may be prescribed memantine (known as Ebixa), which reduces the amount of glutamate — a brain chemical thought to worsen the disease — but this can be prohibitively costly.

Herein lies another factor in the ‘achingly slow’ (as it was recently described) progress in this field: money. Dementia is, most researchers concur, poorly funded. It gets just a twelfth of the annual government funding cancer does (£52 million, as compared to £600 million), meaning that there is one dementia expert for every six cancer specialists. A recent study found there have been 413 failed research projects in the field in the past decade and not a single new dementia drug on the market in 12 years (worldwide, it’s three drugs in 15 years).

At a global dementia forum earlier this year, a stark warning emerged: leading pharmaceutical companies and donors have begun pulling out of this area due to ‘funding fatigue’ caused by a ‘history of failures’ in clinical trials. To get a new drug from the lab to the pharmacy takes an average of ten to 15 years and costs £65 million. Dementia charities such as Alzheimer’s Research UK and the Alzheimer’s Society, which have injected millions, are struggling to pay. ‘We have committed to spending at least £100 million on dementia research over the next decade,’ says Dr Doug Brown, director of research and development at the Alzheimer’s Society. ‘For every £10 that dementia costs the country, only 8p is spent on research to tackle it. The government has committed to double the amount of money it spends by 2025, but this needs to continue to increase and be more representative of the cost.’

Almost every day, it seems, there are headlines promising a ‘cure’ — this year, everyday solutions to dementia have included getting fat, staying thin, eating grapes, drinking coconut water and putting electrodes in our brains. But with the disease still beset by so many fundamental problems, both scientific and regulatory, how close are we really?

First, the screening stage, in which a recent study by scientists at the University of California has shown promising results. By taking blood samples from healthy people and comparing them with those of dementia sufferers, including samples given before their dementia developed, they found that the latter group had similar levels of protein molecules called exosomes in their blood — both before and after the disease took hold.

Professor Christian Holscher, of Lancaster University, one of Britain’s leading Alzheimer’s researchers, hailed the results as ‘very promising’. His research is not entirely dissimilar — revealing that chronic inflammation in the brain may be a trigger for dementia — but he says that lack of support in this country has forced him to continue his work abroad. ‘I’m actually in China, where the Chinese government is very supportive, as their population is ageing and the associated diseases become a real issue,’ he reveals. ‘It speaks volumes that this government funds my research and the British government doesn’t.’

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Progress has been made in development of drugs, too, specifically those designed to target abnormal proteins in Alzheimer’s patients. In March, an experimental antibody called aducanumab, developed by US biotechnology company Biogen, exceeded expectations in early tests by reducing amyloid plaques and showing up to a 71 per cent reduction in cognitive decline. A trial is planned for this year, and scientists say the drug could be on the market by 2018. Professor Chris Dobson, a structural biologist and Master of St John’s College, Cambridge, has had similar success closer to home. His work focuses on the production of tau and amyloid plaques, which are made when proteins in the brain ‘misfold’, and developing compounds to inhibit the process. ‘We have found one, which we’ve dubbed a “neurostatin”,’ he reveals. ‘It’s a protective molecule that reduces the probability of misfolding and the aggregation of toxic species. Now that we understand the mechanism by which proteins misfold, we can focus on potential therapeutics.’

Another exciting field of research is drug repurposing, using substances already on the market. This can save millions on trials and production costs and means the drugs have already passed the costly regulatory procedures that delay the release of most new pharmaceuticals. Positive results have emerged from studies of liraglutide, a type II diabetes drug, which was shown to reduce amyloid plaque build-up in the lab — and is now the subject of a three-year trial of early-stage Alzheimer’s patients in London, Brighton, Southampton, Birmingham, Oxford and Cambridge. There is a link between Alzheimer’s and type II diabetes — sufferers are more likely to develop dementia than healthy people of the same age — so repurposing seems logical, but other double-use drugs are far less obvious.

Dr Atticus Hainsworth, of St George’s University of London, leads a group researching the use of tadalafil, a Viagra-like drug given to men with erectile problems, as a treatment for vascular dementia, the second most common form. The drug works by dilating blood vessels and it is thought it might increase blood flow to the brain, thus limiting degeneration. ‘Tadalafil has already been in 20 million people worldwide, so the side effects are pretty well known,’ he explains. ‘Drug repurposing is fantastically useful.’ He hopes to start recruiting trial participants by the end of this year.

Other avenues of research range from gene therapy (which, it is hoped, could stop brain cells dying, or even replace them) to studies of stem cells, which can be manipulated in the lab to mimic the biological processes associated with dementia. If these seem mundane, a number of scientists are looking outside the boundaries of normal research.

Among these is Souvenaid, a once-a-day drink developed by scientists at the Massachusetts Institute of Technology (MIT) that, they claim, can help the body maintain synapses between neurones, which are gradually lost in dementia. Richard Wurtman, professor of neuroscience and neuropharmacology at MIT, says the drink (which will cost £3 a can and is rich in membrane-making fatty acids) is not a drug but a ‘food for medical purposes’, regulated by the Food Standards Agency, meaning it has been quicker to get to market.

‘We know that there is an interruption of synapse function in Alzheimer’s patients,’ he adds. ‘There are two ways to restore the number of synapses: destroy fewer or make more, which is the goal of Souvenaid.’ Several double-blind, placebo-controlled trials have taken place and the results have been encouraging. ‘My wife and I have been on it for six years, so we’re particularly positive,’ says Wurtman. ‘I really think Souvenaid may be the answer.’

A dementia drink may be a little too much science-fiction for some but it is a marker of how far we have come in thinking intelligently about the causes of dementia and pioneering solutions. A glimpse behind the veil of research shows things are not as bleak as they appear: there may not be a new drug, but progress has far from ground to a halt. Financially, things are looking up. This year, Health Secretary Jeremy Hunt launched the Dementia Discovery Fund, a £52 million research effort, backed by drugs giants and charities.

So what’s next? Jeremy Hunt has pledged that British scientists will find a cure by 2020; the World Dementia Forum a more conservative 2025. Scientists are optimistic. Dr Eric Karran, director of research at Alzheimer’s Research UK, says the deadline is a welcome challenge. ‘We also need to be thinking about prevention,’ he adds. ‘Research suggests that cardiovascular risk factors such as smoking, high blood pressure and obesity could increase the risk of dementia, and better characterising these factors could have a positive impact on the cognitive health of the population.’

It can only go some way to comforting patients, carers and families already devastated by this cruel disease. But, for others, there is hope. ‘The region of the brain affected in dementia — the frontal cortex region — is the very bit that makes us human,’ says Gunn-Moore. ‘We have got to stop people being robbed of their basic humanity. It will take a lot of hard work, but I have no doubt we will get there sooner rather than later. Science today is light years away from where we were a decade ago. The next ten years will be very exciting indeed.’