As far as holy grails in medicine are concerned, you don’t get one much more significant than a cure for dementia. It’s the condition many of us fear most, surveys consistently show, as the disease slowly but inexorably obliterates the mind.
We’ve been waiting for a breakthrough treatment for decades, yet despite billions spent on drug development and research by governments and companies worldwide, the majority of candidates have fallen by the wayside.
Some experimental medicines have even had the opposite effect of the intended effect, actually worsening brain function.
And the only drugs currently available simply tackle specific symptoms of mild to moderate dementia — there is nothing that can slow down the disease or prevent it.
So understandably there was huge excitement and hopeful headlines recently after the first new medicine for Alzheimer’s (the most common type of dementia) in two decades was approved by the U.S. regulator, the Food and Drug Administration.
As far as holy grails in medicine are concerned, you don’t get one much more significant than a cure for dementia
The drug, aducanumab (brand name, Aduhelm), works by clearing the brain of plaque, formed of a build-up of a sticky protein called amyloid-beta — this has been linked to dying nerve cells and is considered a hallmark feature of Alzheimer’s.
But the approval was controversial because despite clearing the plaque, the drug did not significantly improve patients’ symptoms.
‘The problem is there is absolutely no evidence that reducing amyloid-beta also slows down the course of Alzheimer’s,’ says Robert Howard, a professor of old-age psychiatry at University College London. ‘It’s a bit like removing smoke but not putting the fire out. And it is not a benign treatment; the rate of serious side-effects is quite high.’
Indeed, as many as 40 per cent of those who took the highest dose in trials experienced brain side-effects, which included brain swelling, reported the journal JAMA Neurology this month. And 11 people died during the trials. While it’s not clear if these deaths were related to the drug, it was reported earlier this month that the manufacturer Biogen is investigating one particular case of a 75-year-old Canadian woman whose death is thought to be directly connected.
And just last week the European Medicines Agency’s advisory committee gave aducanumab a ‘negative trend vote’, suggesting that the drug will not be approved here (a formal ruling is expected in December).
Aducanumab is also not cheap — it costs $56,000 (nearly £40,000) a year, and there will probably be additional costs for monitoring patients with scans.
Yet still, experts are divided. While some say the drug should be available to those who need and want it, particularly given the lack of treatment choice otherwise, others argue it should never have been approved as it showed no meaningful benefit.
‘There was great hope for the amyloid-lowering drugs but the results from trials have been very disappointing,’ says Gill Livingston, a professor of psychiatry of older people at University College London.
It’s the condition many of us fear most, as the disease slowly but inexorably obliterates the mind
She says aducanumab’s approval in the U.S. ‘just shows how desperate people are for a drug. Many people would still take it despite the risks, because we have nothing else that promises to slow down brain decline’.
Another concern is that its approval sets a precedent for other drugs to be given the green light for Alzheimer’s even if they, too, don’t prove they can slow down brain decline and yet cause significant side-effects. This is highly probable because all of the frontrunners in the pipeline target the same pathway as aducanumab.
And some experts say millions more could be wasted targeting a mechanism that doesn’t yield benefits, when the focus should be shifted elsewhere, including to lifestyle changes we can all take to protect ourselves.
A much-hoped for breakthrough
The need for a breakthrough in Alzheimer’s treatment is unequivocal. Around half a million Britons have the disease and the only available treatments, such as donepezil, rivastigmine and galantamine target brain chemicals to relieve symptoms, but usually become less effective as the condition worsens.
The problem is that we still don’t understand what causes Alzheimer’s. The conventional view is that amyloid-beta plaques build up and disrupt communication between nerve cells, ultimately causing them to die.
Based on this logic, the solution seems straightforward: clear the plaque to cure Alzheimer’s.
‘But aducanumab isn’t the transformative drug for Alzheimer’s as it generally had a small effect,’ says Dr Tom Russ, a consultant psychiatrist and director of the Alzheimer Scotland Dementia Research Centre at the University of Edinburgh, who was involved in the trials. ‘But Alzheimer’s is such an awful illness that anything which has an effect could be of value.’
Others argue that the clinical need justifies the level of risk associated with new drugs such as aducanumab.
Dr Liz Coulthard, a dementia neurologist at North Bristol NHS Trust, who was involved in aducanumab trials, explains: ‘Despite not meeting all of the clinical endpoints in its trials, aducanumab looks promising and I strongly believe we should approve it.
‘I understand reservations over the data, but we can’t shut down options for new Alzheimer’s drugs; we have to treat the right patients who may benefit from them.
‘For example, I see people of working age or in early retirement who have mild cognitive problems. This is a time where we could intervene to stop the condition worsening with the right treatment and yet we have no disease-modifying options for them.
‘They’d appreciate anything and should be able to decide whether to take this drug, knowing the potential benefit and risks.’
Some are more emphatic — Professor Bart De Strooper, director of the UK Dementia Research Institute describes aducanumab as ‘a game changer’.
‘There is always a gamble you take when approving new therapies. But as we have seen during the Covid-19 pandemic, it is possible to move much faster than usual because of the clinical need for a treatment.
‘Yet no one sees dementia as an acute problem so there is no sense of urgency, which I disagree with.
‘Aducanumab is the first drug to have a significant effect on amyloid plaques. I think we’ll see greater benefits in subpopulations of patients, and timing is crucial.’
Are we looking in the wrong direction?
But some researchers believe targeting amyloid-beta is misguided, because reducing the plaque build-up didn’t translate into a meaningful benefit to patients in the aducanumab trials.
Also, crucially, many people have this plaque build-up but never develop symptoms of Alzheimer’s, says Dr Russ. ‘Based on studies from brain scans in living people as well as samples taken in post-mortems, lots of people have lots of amyloid in their brains and yet can live long lives with no symptoms.
‘There’s no doubt that targeting amyloid is an important avenue to pursue, but it’s become the only one,’ he says.
Amyloid-beta actually occurs naturally in the brain, where it’s thought to have an antimicrobial effect and play a role in the transport of cholesterol (which is needed to help release brain chemicals between nerve cells and keep them functioning well).
It is its accumulation that seems to be harmful, says Dr Russ. ‘But even with amyloid build-up, we still don’t know who will progress to have symptoms of Alzheimer’s and who won’t — so it can’t be the whole story.’
And rather than continually throwing good money after bad ideas, we have to look at other factors methodically, says Professor Livingston. ‘People are attached to an idea that amyloid is a cause and targeting it makes a difference — we keep trying and nothing quite comes through.
‘We must acknowledge when something isn’t working and move on, regardless of how much has been spent on the research.’
Professor Howard concurs: ‘Our simplistic view that Alzheimer’s is caused by amyloid just isn’t right.
‘Plaques have been found in Alzheimer’s patients’ brains since the 1900s, and we still haven’t determined their role in disease. Our understanding of the disease might be completely wrong.’
Indeed one theory is that amyloid is a good thing, and may be part of the way the brain adapts to Alzheimer’s, rather than a cause.
‘We don’t even know what happens long term if we remove amyloid because patients who take the amyloid-lowering drugs are not followed up after studies end,’ adds Professor Howard.
Untangling the root cause
So if amyloid is the wrong target, where should the focus be? One option is tau, another protein but one found inside brain cells — it misfolds and forms tangles that are thought to interfere with the way cells communicate. The presence of these tau tangles is another hallmark of Alzheimer’s.
These studies have also revealed that some Alzheimer’s patients have lots of tau tangles, and yet no amyloid plaque — with research suggesting that cognitive decline is closely linked to the number and location of tau tangles.
What causes the tau to become tangled is unclear, but it can be worsened by the plaque and by inflammation in the brain which ensues as a result.
Based on this knowledge, some researchers believe that it is the tau tangles that determine the severity of symptoms — and so targeting this protein might have a more meaningful effect on a patient’s day-to-day life than targeting the amyloid plaque.
Trials into molecules that prevent tau tangles are under way, says Professor Howard, although it remains early days for these.
However, one tau inhibitor is in advanced trials, led by Aberdeen-based manufacturer TauRx Therapeutics — 600 patients will be given a high or low dose of the drug (code-named TRx0237) or a placebo (preliminary results may be available next March).
‘We think targeting treating tau would yield faster effects than if targeting amyloid,’ says Professor De Strooper. ‘If we want to stop amyloid building up we would need to target it much earlier in life. What’s exciting is that some companies are now looking into combining both the amyloid and tau drugs into a single treatment.’
Hope for a vaccine to prevent dementia
Another option is to vaccinate people against dementia – U.S. researchers are already testing a nasal vaccine on people with early Alzheimer’s.
The vaccine contains a compound, Protollin, that’s thought to mobilise the immune system’s white blood cells to ‘migrate to the brain and trigger clearance of beta-amyloid plaques’, the researchers from Brigham and Women’s Hospital said when they launched the trial this month. The hope is that this could treat Alzheimer’s and prevent it in people at risk.
The University of Leicester is also testing a potential vaccine, albeit so far in mice. They say they’ve discovered a version of amyloid-beta that specifically causes Alzheimer’s.
‘Trials so far have been targeting amyloid-beta plaque, but this is not a cause of disease but a consequence of it,’ says Mark Carr, a professor of biochemistry and chair of the Antibody-Assisted Drug Discovery Consortium at the university.
Using the analogy of measles, he explains ‘to cure it you don’t treat the spots, you target the virus that causes disease – we identified a rare form of amyloid-beta that causes Alzheimer’s and when we targeted it using an antibody in mice, we were able to spectacularly slow disease progression’.The researchers identified that the type of amyloid-beta involved was hairpin shaped: ‘No-one had ever suggested amyloid-beta would form this type of structure – but this could explain why drugs so far haven’t been effective,’ says Professor Carr. ‘When we identified the specific structure we were able to engineer an antibody to selectively target it.’
The researchers believe the antibody, called TAP01 and given via injection, could work as a drug, slowing Alzheimer’s in its tracks, and a related vaccine could prevent it in people at risk. (This would require a screening process to identify people with very early signs of Alzheimer’s.)
‘I have worked on lots of therapeutic antibody studies and can think of only one other case where experiments in mice have been so spectacularly successful and that was for an antibody to treat osteoporosis,’ says Professor Carr. (This antibody drug, called Evenity, is now prescribed and builds new bone in people with osteoporosis.)
This is ‘a very different, interesting approach’, comments Professor Howard. ‘But it is still being studied in mice, so is a long way from fruition,’ he adds, sounding a note of caution.
‘From experience, we cure dementia in mice at least three times a week, but when we take it into human studies the results aren’t the same.’
Surprise benefit of having the flu jab
Intriguingly, recent research suggests that routine vaccinations may help reduce Alzheimer’s risk, with the incidence of the disease much lower in older people who’ve been vaccinated against other diseases, such as flu, according to a study of over 60s published earlier this year by Saint Louis University School of Medicine in the U.S.
This showed that once people had been vaccinated for six years or more, their dementia risk dropped by an average of 14 per cent. One theory is that repeated annual jabs strengthen the ageing immune system — in particular, immune cells in the brain called microglia — to the point where it can prevent or repair the damage that causes dementia.
Targeting the microglia may also play a role in treating Alzheimer’s — while these cells kill off foreign invaders and toxic debris (including amyloid plaque in its early stages), this switches on inflammatory pathways — it’s thought that in some people, the microglia become over-sensitive, reacting to inflammation anywhere in the body, even that triggered by infections or the common cold, and this triggers a cycle of more inflammation and degeneration of healthy brain cells.
‘There is really convincing evidence for the role of inflammation in dementia and Alzheimer’s,’ says Dr Coulthard.
Professor Howard agrees: ‘There’s a lot of interest in inflammation and specifically targeting microglia, with the idea that they are overly activated and destroy brain tissue rather than protect it.
‘It is possible that some anti-inflammatory drugs can help reduce this effect,’ he adds. ‘We know people who take non-steroidal anti-inflammatory drugs (such as ibuprofen) are less likely to develop dementia.’
But finding the right approach is the key — he cites a trial using minocycline, an antibiotic prescribed for acne that also has anti-inflammatory effects, which didn’t slow down patients’ dementia.
‘Tau tangles and amyloid plaques were the first targets for treatments because that’s what you physically see in the patient,’ says Professor De Strooper. ‘But we also have inflammatory processes in the brain that may underpin both of these — potentially causing the amyloid build-up as well as exacerbating tau tangles.’
Sleeping off dementia?
A good night’s sleep may also be a key preventative factor, suggests Dr Coulthard. Sleep disorders such as sleep apnoea (where the tissue in the throat collapse during sleep, causing breathing to stop for up to ten seconds) raise blood pressure and cardiovascular risk — both linked to dementia.
But separately, in a stage of sleep known as non-REM, which occurs just after we drop off, amyloid and toxins are cleared from the brain.
‘With interrupted, bad sleep you don’t get into this [non-REM] stage so don’t go into this clearing process — raising the risk of amyloid build-up,’ says Dr Coulthard.
Other scientists are now investigating whether drugs for insomnia could help prevent dementia in people at risk, or treat early signs of the disease.
So what can you do now?
While we wait for the outcome of clinical trials, there could be lifestyle choices that may help us lower our risk of Alzheimer’s. These are particularly important if you have a family history.
‘It always makes sense to prevent rather than focus on treating conditions — but we must prioritise both equally,’ says Professor Livingston. ‘Sadly much more money has gone to the so-called magic bullet than into prevention.’
The 2020 Lancet Commission on Dementia Prevention, Intervention and Care — led by Professor Livingston — concluded that 40 per cent of dementia cases could be prevented or delayed by tackling 12 modifiable risk factors, including losing excess weight, controlling blood pressure and diabetes, lowering alcohol intake, and exercising regularly.
The significance of this is borne out by the fact that while the number of people with dementia is increasing — as we have an older population — the rate per 100,000 has decreased considerably, by 25 per cent in 20 years, says Professor Livingston. ‘This is due to improvements in our education, smoking cessation and healthcare — which suggests that preventative measures can have an impact.’
A study reported just this month found that a diet packed with vegetables, fruit, beans and tea and coffee seems to protect against dementia. Researchers from National and Kapodistrian University of Athens in Greece, looked specifically at intake of foods thought to reduce inflammation — a third of the 1,000 study volunteers (all aged over 70) who ate the least of these foods were three times more likely to develop dementia during the three-year study, compared with the third who ate the most.
The difficulty is that there is a lack of direct evidence from robust clinical trials for lifestyle interventions to prevent dementia, says Dr Sebastian Walsh, an academic clinical fellow at the University of Cambridge, but the emerging evidence is pointing clearly towards a benefit of maintaining a healthy lifestyle (e.g. exercising more, eating well, keeping your brain active) reducing dementia risk, and it’s definitely worth trying because this prevents other diseases too, and unlike taking drugs there are no side-effects.
‘There have been attempts but it is difficult with lifestyle measures and Alzheimer’s — studies that monitor brain decline show that dementia develops over decades, so it’s tricky to extend expensive trials over a long period that you need for meaningful data.
The problem, he says, is that while a treatment has been prioritised, investment towards improving prevention and care for patients has been lacking.
‘What we don’t need is drugs that don’t work lauded as magic bullets wasting millions — we have to spend money on things that will change people’s lives and be honest with people about where we are.’
Lack of funding remains an issue in Alzheimer’s and dementia research, says Professor De Strooper. There are more than 20 times as many clinical trials and publications on cancer than dementia, for example, despite it affecting more people, he says. (According to the UK Dementia Research Institute, 74,000 clinical trials have been run in cancer since 2000 compared with fewer than 2,400 in Alzheimer’s; and 512 drugs have been approved by the FDA for cancer in the same timeframe, compared with six for Alzheimer’s.)
‘We are not able to understand what’s going on and what causes Alzheimer’s because we don’t have basic science knowledge yet.’ says Professor De Strooper.