91av

NEW drug will finally cure Alzheimer’s! Sound familiar? Seemingly every other week, the results of one preliminary trial or another promise that a game-changing drug for Alzheimer’s disease is just around the corner.

Check back a few months later, though, and all mention of the drug has vanished, save perhaps for a terse story about a failed trial. Almost all clinical trials of new drugs to combat Alzheimer’s fail. No drug has bucked the trend in 20 years, but you wouldn’t know it from the constant promises of a breakthrough.

Last November, after the failure of a particularly high-profile trial, for some the jig was up. “There are no treatments that can slow or reverse this devastating condition,” says Bryce Vissel at the University of Technology in Sydney, Australia. “There is no question that we have to look at Alzheimer’s in a different way.” So are we heading in the right direction, or do we need to rip up all the textbooks and start over?

Alzheimer’s is the most common cause of dementia, and by some metrics its prevalence is rising. Alzheimer’s Disease International estimates that in 2015, 46.8 million people worldwide had dementia, a number that is set to double every 20 years, mostly because of an increasing number of older people in developing countries like India and China, leading to a global healthcare crisis.

The lack of meaningful treatments is not for lack of trying. The pharmaceutical industry has poured billions into research – Eli Lilly alone has spent £3 billion over three decades trying to develop a successful drug, and the US National Institutes of Health has spent in pursuit of treatments.

Despite the money and effort, the last Alzheimer’s drug licensed in the UK can only treat the condition’s symptoms – it doesn’t halt the underlying deterioration. At best, it can buy someone a bit more time.

“There is no question that we have to look at Alzheimer’s in a different way”

So where has all that money gone? Into experimental drugs that garner much press coverage as they clear various early clinical stages (see diagram). However, none of the have cleared all the hurdles.

Most have focused on disrupting the sticky plaques that Alois Alzheimer found more than a century ago in the brains of people who had died with the dementia to which he gave his name. As these plaques clog up the brain and destroy brain cells, it is thought they take with them the vital memories and mental functions that the cells underpin. Get rid of the plaque, the thinking goes, and you get rid of the disease.

The plaques are a build-up of a protein called beta-amyloid, so it is that substance that most of the drugs have targeted. Eli Lilly’s drug solanezumab was an especially promising example. It attacked the precursors that form new beta-amyloid, and was billed as the best hope yet. The company sent out several press releases about exciting preliminary results before the end of the trial.

Then it failed. The results of the early trial, they concluded, were simply not significant enough to warrant putting a drug on the market. For many, the failure of this trial was the straw that broke the camel’s back. “Is this the end of the amyloid hypothesis?” asked after the failure. “We must urgently get back to the biology of this disease,” says Vissel. That doesn’t mean throwing out the enormous body of work on beta-amyloid with the bathwater, he says: “Any holistic view of the data will have to account for it.”

However, there has been growing recognition that . Lost amid the almost single-minded focus on the are cases in which people have died of what is supposedly Alzheimer’s, but postmortem examinations revealed no plaque in their brains. Equally baffling postmortems revealed enormous plaque build-up in the brains of people with extraordinary memories.

The strongest evidence for a relationship between removing these deposits and improvements in brain function comes from mice that have been bred to mimic symptoms of Alzheimer’s. Part of the reason human trials have been unsuccessful is that plaque eradication doesn’t translate into similar cognitive improvements in people.

Could the plaques be a symptom rather than a cause? According to one hypothesis, plaques may actually be a defence against bacterial invasion. In fact, they may play a number of roles in a disease that could have many contributing factors (see “Beyond the usual suspects“).

But plaques may also play a part in healthy brains. There is growing evidence that the brain may need some amyloid protein – in one trial, removing it entirely resulted in side effects such as brain swelling. “Amyloid is in the brain for a reason,” says Vissel. “We still know so little about its normal role.”

Against this backdrop, Eli Lilly executives remain optimistic about beta-amyloid. “We are on the cusp,” John Sims, senior medical director at Eli Lilly, told 91av last December at the annual in San Diego, California, where the firm announced the failure of solanezumab. “With each little trial, we’re taking one step closer to understanding the pathology better.”

What can explain the unchanged enthusiasm after all the failures? Some wonder if it’s because of the amount of money that has already been sunk into this. “There is an element of that,” says David Reynolds, chief scientific officer at Alzheimer’s Research UK. “If you’ve invested a lot, you must get to the finishing line,” he says.

But Sims insists that even though the effects seen were modest, they were consistent across all trials – and across all the cognitive tests applied to the patients. “That means they must collectively be showing mild efficacy of the drug.” Now, the company and others are looking to boost that efficacy with other agents that tackle different aspects of plaque. Sims is orchestrating a trial of a drug that switches off production of plaque in the brain.

Rudolph Tanzi of Massachusetts General Hospital in Boston, who isolated the gene that makes amyloid, doesn’t count the hypothesis out yet. “To get so close to statistical significance with a drug that doesn’t even dissolve the amyloid that’s already in the brain is highly encouraging,” he says. Tanzi is excited about the prospect of mixing a solanezumab-type drug with another drug being trialled, aducanumab, which attacks existing plaques.

No cause for alarm

If all these drugs individually have moderate effects, it will redeem the beta-amyloid hypothesis, and Tanzi thinks, point the way to a multi-drug approach to treatment.

One drug might remove existing plaque, while another keeps new plaques from forming. “I can see aducanumab being used as a kind of liposuction for the brain for a month or so,” he says, and then a different regimen – which, like solanuzemab, disrupts amyloid formation – prevents further accumulation thereafter. This approach would be similar to how cholesterol blockers are given preventively to people with high cholesterol.

Several such drugs are in late-stage clinical trials that will conclude over the next three years, beginning this summer. Their results should establish once and for all whether hitting amyloid benefits humans.

If drugs don’t make a difference, there are other methods waiting in the wings, including using light therapy to boost a kind of brain wave that disrupts plaques.

While we wait for the verdict, we can take solace in the finding that we can do things to prevent dementia. There is growing evidence that certain behaviour reduces the chances of developing it, especially frequent exercise, sensible eating and avoidance of smoking and excessive alcohol. What’s good for your heart, it turns out, is good for your brain.

This article appeared in print under the headline “The Alzheimer’s problem”