Is the $50bn Alzheimer’s hypothesis a dud?

The trial failures of potential curative drugs have divided Alzheimer’s researchers. Australian Doctor reports.

Late last year, the global Alzheimer's community held its collective breath as it waited for the trial results of the latest potential ‘cure' for the disease.

Some early successes with a drug called solanezumab (‘sola' for short) had pumped up expectations that a major breakthrough was near.

"After a decade of no new therapies for dementia, [solanezumab] represents an exciting step forward," enthused Dr Doug Brown, head of research at the Alzheimer's Society in the UK.

Like almost all treatments that have been trialled for Alzheimer's over the past decade, sola clears sticky blobs of the protein beta-amyloid from the brain. These blobs or plaques are known to accumulate in people with the disease, probably decades before symptoms become apparent.

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The consensus driving much of the search for a cure is that the plaques are what's causing Alzheimer's, with its classic symptoms of confusion, memory loss, mood changes and inability to cope with daily tasks. They do this by disrupting communication between brain cells, and eventually killing them.

It's what's known as the ‘amyloid hypothesis' and its implications are pretty straightforward: get rid of beta-amyloid from the brain, and you can slow, halt or even reverse the ravages of Alzheimer's.

Sola works in mice. Given a shot of the drug, mice that had been genetically altered to develop Alzheimer's underwent a miraculous change. From doddering around their cage in a daze, they went to shooting through the laboratory maze.

Trial troubles
But when the drug's manufacturer, Eli Lilly, moved to testing it on actual people, things started to fall apart. Two phase III trials failed to improve cognition, although they did offer a glimmer of hope for patients with early disease.

Amid a flurry of media attention in the medical community, last November, Eli Lilly announced that its third trial involving people with mild Alzheimer's and demonstrable beta-amyloid accumulation in the brain showed sola had no statistically significant advantage over placebo. The company said it would continue its work on solanezumab, but wouldn't be seeking regulatory approval any time soon.

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The results were, in fact, the worst of both worlds, in that the drug did clear the amyloid plaques (as required under the amyloid hypothesis), and yet this seemed to do nothing to slow disease progression.

The results prompted some to claim the orthodox view of the cause of Alzheimer's was all wrong, and that $50 billion dollars had been wasted researching interventions based on the amyloid hypothesis over the past 10 years.

"What the amyloid hypothesis does is capture the interest of the media, the drug companies and the carers' societies. But in terms of pathogenesis, it seems to be wrong," says Professor David Le Couteur, director at the Centre for Education and Research for Ageing at the University of Sydney.

The origins of the amyloid hypothesis go right back to Dr Alois Alzheimer himself, who, in 1906, carried out an autopsy on a dementia patient and discovered a dense distribution of plaques throughout the patient's brain.

Dr Alois Alzheimer's discovery of plaques in alzheimer's patients was the catalyst for the amyloid theory.

But it wasn't until the 1980s that researchers, including Professor Colin Masters from Melbourne's Florey Institute, identified the protein that made up these plaques and started pushing the amyloid hypothesis as a cause of Alzheimer's.

Of mice and men
Over the next decades, hundreds of research papers were published bolstering the thesis, and drug companies poured vast amounts of cash developing drugs with the aim of clearing the brain of beta-amyloid.

But as the companies developed and trialled the drugs, a pattern emerged. When tested in mice, these drugs banished Alzheimer's symptoms, time after time. But in humans, they bombed.

The trial failures — particularly that of solanezumab — have torn the Alzheimer's research community in two, with the amyloid true believers on one side and the increasingly confident naysayers on the other.

Professor Ralph Martins (pictured left), who collaborated with Professor Masters on the critical research that identified amyloid pathology in Alzheimer's, remains in the true believer camp.

He says the problem is not with the amyloid-busting drugs per se. It's that they've been tested in the wrong people.

"If you look at the brains of people diagnosed with Alzheimer's, they're already severely damaged in the regions involving memory and learning," he says. "We need to act before the damage is done and target people well before the onset of symptoms."

Professor Martins, who is chair in aging and Alzheimer's disease at Edith Cowan University and has been involved in many Alzheimer's trials, says the idea is to target people who do not yet show signs of dementia, but already have an accumulation of beta-amyloid in the brain.

"We now have imaging that can identify how much amyloid people have in their brains. But the technology is too expensive and invasive to be used for screening. So we're looking at the eye as a means of screening. We think there are changes in the retina that we can measure that correlate with amyloid in the brain."

But the naysayers shake their heads at the idea of putting asymptomatic people on expensive drugs with unpredictable side effects.

Professor Le Couteur says that, in any case, even the much-vaunted correlation between amyloid build-up and Alzheimer's symptoms just isn't there.

Alzheimer’s key figures
  • Around 354,000 Australians are living with Alzheimer’s and other dementia-related illnesses.
  • Without a medical breakthrough, that figure is likely to rise to 900,000 by 2050.
  • Three in 10 people over the age of 85 and one in 10 over 65 have dementia.
  • Dementia is the second leading cause of death in Australia.
  • On average, Alzheimer’s symptoms are noticed by families three years before a firm diagnosis is made.
  • Australia faces a shortage of more than 150,000 paid and unpaid carers for people with Alzheimer’s and other forms of dementia by 2029.
  • Annual direct health and aged care system expenditure on people with dementia is around $5 billion and rising.

Source: Alzheimer’s Australia


Magic bullet
"It's the attraction of the idea of a magic bullet, and the failure to understand the difference between disease and ageing," he says.

Professor Le Couteur points to the work of Professor Carol Brayne, a leading UK dementia researcher who runs a brain bank and dementia epidemiology program at the University of Cambridge.

"She's done lots of post-mortems on people who were well characterised before they died, and basically she's found very little correlation between the classic features of Alzheimer's disease and beta-amyloid."

He says beta-amyloid might be a good marker in the relatively rare young-onset Alzheimer's, "but once you get to older people, where the real problem is, the relationship between beta-amyloid and cognitive function just falls apart".

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Professor Martins disagrees. "That's been the classic reply of the naysayers," he says.

"They're right, in that we all get more amyloid in the brain as we age. But what we've found in our work is that the rate at which it increases is important. It's not just having amyloid in the brain; it's how much and how fast it's rising."

But he concedes that some people seem to deal with amyloid much better than others, and that it's an area that needs more research.

"Maybe they can make more natural antioxidants in their body that neutralise the amyloid," he speculates.

The split between the naysayers and true believers isn't just about what causes Alzheimer's; it's about what the future of Alzheimer's treatment should look like as well.

Professor Martins remains optimistic about drug therapies for the disease.

"I've been working in the field for 30 years, and the rate at which we're progressing is tremendous," he says. "I'm very, very confident that there will be drugs coming onto the market. In fact, I'm confident we already have the drugs, and that they have been tested in the wrong setting."

Ageing process
But Professor Le Couteur says the way ahead is more likely to be in the less sexy area of prevention than drug treatment.

"We already have disease-modifying interventions right now — stopping smoking, exercising, and diets rich in vegetables and unprocessed fresh food. We know this because we have studies and clinical trials to show it."

For the 354,000 people already living with the disease in Australia, as well as their carers, that will offer little comfort.

The idea of a neat answer to the devastation of Alzheimer's is seductive, Professor Le Couteur admits.

"But when you work in geriatric medicine, you realise that everything is multifactorial, everything is embedded in multimorbidity and everything has an underlying ageing process related to it.

"The idea that there's a single thing that could fix a problem as complicated as dementia doesn't seem terribly likely."

Alzheimer’s disease timeline

1906:  German physician Dr Alois Alzheimer describes Alzheimer’s pathology for the first time
1968:  First tool for measuring cognitive and functional decline
1984:  Beta-amyloid is identified as the main component of the brain plaques that are the hallmark of the disease
1993:  The APOE4 gene is identified as a risk factor for Alzheimer’s
1999:  An ‘Alzheimer’s vaccine’ is successful in mice, but later fails in  humans
2006:  Alzheimer’s trial of NSAIDs fails
2010:  Antihistamine drug latrepirdine (Dimebon) fails in phase III trials
2011-2015:  Ten anti-amyloid drugs fail in trials
2016:  Solanezumab fails in a trial for early disease
2017:  Around 80 agents are still under investigation for Alzheimer’s disease

Hugo Wilcken is an Australian Doctor Group reporter.