Alzheimer's: we can't afford to forget it

Hazel Hawke was known for her sharp mind. So it came as a shock in 2003 when she announced on prime-time television that she had Alzheimer's disease, or the "big A" as she liked to called it.

The CEO of Alzheimer's Australia, Glenn Rees, says at the time, the personal disclosure from the former wife of a former prime minister was a "bombshell". Hazel Hawke was the first high-profile Australian with the disease to talk about it openly, he says. "We hadn't really had anyone speak out before."

In May this year, a decade after her public admission, the social-rights campaigner and enthusiastic pianist died from complications of the disease. A memorial was held at the Sydney Opera House on Tuesday.

It is thanks to people like Hawke and other campaigners that awareness of Alzheimer's has entered the public conscience. The disease is not something society can afford to forget.

"The threat of Alzheimer's and other neurological diseases is extraordinary," says Dr Bryce Vissel, the head of neurodegenerative research at Sydney's Garvan Institute of Medical Research.

The statistics are stark: about one in three people over 85 and one in 10 over 65 will develop the condition. The World Health Organisation estimates the cost of caring for people with dementia, of which Alzheimer's is the most common form, totals about $600 billion a year worldwide. In Australia, a 2009 Access Economics report projected spending on dementia would outstrip any other health condition by the 2060s.

"While rates of diseases like prostate cancer are going down, the rates of Alzheimer's are going up and there is no change in sight," says Professor Juergen Gotz, the director of the Clem Jones Centre for Ageing Dementia Research at the Queensland Brain Institute.

Research into the disease, which was first described a century ago, has been steadfast, with most insights uncovered by scientists in the past three decades. But despite significant progress, the field has encountered a series of treatment setbacks in the past few years.

Last year, several key drugs, which many hoped would lead to a cure for the disease, failed to improve the memory of patients in clinical trials. Not only disappointing, the drug failures also call into question the leading hypothesis of the cause of the disease - a build-up of plaque in the brain - and how best to treat it.

The head of Neuroscience Research Australia, Professor Peter Schofield, an Alzheimer's researcher himself, says the discipline has had to recalibrate and change gears.

Some researchers, including the Garvan Institute's Vissel, see an opportunity for those whose theories of the disease have been outside the mainstream to stand up and be noticed. "We've been working on the idea that it's inflammation in the brain that's the cause of the degeneration and the symptoms," he says.

Australian scientists have also made significant progress diagnosing the disease at earlier stages, says Professor Ralph Martins, the research director of the McCusker Alzheimer's Research Foundation.

"This has propelled Australia to the forefront of Alzheimer's research," he says.

Australian scientists were part of an international consortium that last year reported changes in brain proteins and other related signals could be detected up to 25 years before patients showed declines in their memory.

The findings pave the way for trialling drugs to prevent the disorder, several of which will begin later this year, says Martins.

But the country's continued success in Alzheimer's research depends on funding. Compared with other diseases - cancer, heart disease, diabetes - Alzheimer's and other neurological disorders receive a fraction of research budgets.

The most recent National Health and Medical Research Council grants dished out $162 million to cancer research, $93 million to cardiovascular disease research and $63 million to diabetes research. Dementia researchers received $21 million.

Given the growing prevalence of Alzheimer's and its burden on the healthcare system, research should be a government priority, says Vissel.

"When scientists work out the treatment, its impact on suffering will be enormous and will save governments billions of dollars. We must succeed," he says.

What sets Alzheimer's apart from other serious and prevalent disorders is how much we still have to learn about it.

More than a century has passed since Alois Alzheimer first described the condition in a middle-aged woman with memory loss - upon her death he found her brain riddled with a substance that mimicked tooth plaque - and yet the exact biological cause remains elusive.

Scientists have theories, some with strong evidence, but without knowing the precise trigger that sets off the disease; even diagnosing the condition has been difficult. Until a few years ago, doctors could not be sure a person had Alzheimer's until an autopsy was performed, revealing clumps of plaque in their brain tissue. Advances in imaging techniques mean the disorder can now be detected with brain scans.

When scientists, including Australian Colin Masters, discovered in 1984 that the disease's characteristic plaque was made of a protein called beta amyloid, the field finally had something to focus their attention and research. The amyloid hypothesis was born, says Martins.

According to this theory, the disease occurs when beta amyloid accumulates in the brain, causing damage and eventually the death of nerves cells and their connecting synapses.

Scientists predicted that if levels of the protein were reduced, the disease could be slowed. And if treatment was started early enough, perhaps it could also be prevented.

The amyloid hypothesis received further support when scientists identified genes, the first in 1987, linked to beta amyloid production in people with an early onset form of familial Alzheimer's. When mutated, these genes resulted in a protein oversupply.

Further evidence emerged when mice, genetically engineered to produce too much beta amyloid, developed Alzheimer's. A few years later, other groups showed the disease could be reversed in rodents by switching off the genes.

This is where Vissel believes things started to go wrong. The faulty genes are found in only a small subset of people with early onset Alzheimer's and yet the insights from these studies were being used to direct the diagnosis and treatment of the far larger group who develop the disease sporadically in older age, he says.

"Things jumped too far ahead of themselves," says Vissel.

Fast forward a decade to the predicament scientists now find themselves in: while drugs targeting beta amyloid production have succeeded in removing or reducing plaque in the brains of Alzheimer's patients, they have had almost no effect on restoring their memories.

Gotz and others believe the field's single-minded focus on the amyloid hypothesis meant other theories, such as the role of another protein called tau, were not pursed with the same rigour. "I think the field has been quite dogmatic," he says.

While beta amyloid accumulates in the brain of Alzheimer's patients, it is tau, which forms twisted structures known as tangles, that aggregates in the region where nerves cells die. Gotz believes beta amyloid executes its toxicity through tau.

But many scientists have only recently accepted tau is a good drug target, he says.

Despite the disappointing drug trials, Martins believes there is still compelling evidence beta amyloid is critical to disease development.

A CSIRO co-ordinated study of more than 1000 people, some healthy, some with Alzheimer's or mild cognitive decline, found 60 per cent of healthy people who display traces of amyloid in the brain will develop Alzheimer's. In the six years the Australian Imaging, Biomarkers & Lifestyle Flagship Study has been running, it has found only 1 per cent of people without the protein develop dementia.

All of the researchers Fairfax Media spoke to still hold out hope for the beta amyloid drug targets. They say the problem is unlikely to be the drugs themselves, but the stage they were administered to patients, most of whom had well-established Alzheimer's with severely damaged nerve cells that were beyond recovery.

"I'm very confident that most of the drugs were pretty good, they were just introduced too late," says Martins.

Vissel, on the other hand, is focusing on something different. He accepts, like most scientists, that both tau and beta amyloid are important, but his research suggests it is brain inflammation - the result of injury or infection - that triggers the toxic proteins to aggregate.

There is good evidence that beta amyloid is released in response to, and exacerbates, inflammation, he says. A mice study in 2009 also showed inflammation prevents nerve cells regenerating in animals with Alzheimer's.

His theories are slowly gaining acceptance. "I think he's on the money with inflammation," says Martins, although he says it is hard to tease out which comes first, inflammation or beta amyloid.

Martins says the real hope now lies in trials for preventive treatments.

This year, several international research groups will test whether various drugs, including some of the previously unsuccessful anti-amyloid drugs, can stall the onset of the disease in people with genetic forms of Alzheimer's or those with an increased risk. Several trials will be conducted in Australia.

But the future of such Alzheimer's research in Australia depends on support from government, scientists say. Alzheimer's Australia's Glenn Rees hopes that dementia's inclusion as a national healthy priority in 2012 will encourage federal and state governments to better fund research projects and increase the number of scientists tackling the problem.