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, 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 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 United States regulator, the Food and Drug Administration (FDA).
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, the manufacturer Biogen is investigating one particular case of a 75-year-old woman in Canada whose death is thought to be directly connected.
Earlier this month 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, 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.
She says aducanumab's approval in the US "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. 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. Dr Liz Coulthard, a dementia neurologist at North Bristol NHS Trust, who was also 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 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 (needed to help release chemicals between nerve cells and keep them functioning).
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, he says, 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. These tangles are a hallmark of Alzheimer's, seen in post-mortem studies.
These studies have also revealed that some 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, some researchers believe that it is the tau tangles that determine the severity of symptoms - and so targeting them might have a more meaningful effect on a patient's day-to-day life than targeting the amyloid.
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 maker TauRx Therapeutics - around 600 patients will be given a high or low dose of the drug (codenamed TRx0237) or a placebo (preliminary results may be available next March).
"We think targeting 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."
© Daily Mail
