Could an anti-stress drug tackle Alzheimer’s?

Despite the lack of progress in dementia research, a new study may still provide hope...

AFTER decades of research, scientists have failed to find any effective treatment for Alzheimer’s disease, and, following futile efforts, last month pharmaceutical giant Pfizer announced it is ending its own dementia research programme.

The reason for this lack of progress is beginning to emerge: the scientific idea underpinning the majority of treatments and clinical trials is fundamentally flawed.

Scientists have spent years developing treatments that target a protein called amyloid, which plays a vital role in healthy nerve cell function, but can become corrupted — sticking together to form damaging clumps or plaques, which destroy nerve cells.

This leads to gradual but irreversible loss of brain function, and the symptoms of Alzheimer’s.

Researchers believed treatments that break down amyloid plaques would stop the march of Alzheimer’s. Yet virtually every drug tested has failed in large-scale trials.

Experts argue this focus on amyloid has led to the sidelining of other avenues for the treatment or prevention of Alzheimer’s, and the role of lifestyle factors such as diet, stress and sleep.

THE evidence that amyloid is critical in Alzheimer’s disease is simply overwhelming,’ says Sir Simon Lovestone, a professor of translational neuroscience, explaining that plaques can be seen in brain scans and postmortem examinations of Alzheimer’s patients.

‘However, this doesn’t mean removing amyloid will be an effective cure and there’s no good evidence that it makes a difference to the progression of the illness.

‘Also, most Alzheimer’s patients are diagnosed once symptoms such as memory loss start, and by that time amyloid plaques will have been growing undetected for decades. The damage has already been done.

‘It’s like somebody breaking their leg, then having a splint put on it four years later. It doesn’t work. We need to treat people at the time the plaques start forming and begin trials earlier, to stop damage in the first place. The ideal person who should enter clinical trials is someone like me — in their mid-50s with no obvious symptoms — not someone with advanced Alzheimer’s.’

Unfortunately, it is extremely difficult to identify those people who will benefit from treatment.

To tackle this problem, Professor Lovestone and his team have launched a project to detect the earliest signs of Alzheimer’s.

The Deep and Frequent Phenotyping study is examining 250 people aged 55 to 80 using a barrage of tests, ranging from blood and DNA analyses to hightech brain scans and memory assessments.

The volunteers will be monitored to see if they develop Alzheimer’s, then researchers can look back at the results in search of tell-tale signs that could signify early disease, such as activity patterns in the brain or chemicals in the bloodstream. These markers could then be developed into diagnostic tests and may make drugs — even those that target amyloid plaques — more effective.

Other research groups are turning away from amyloid and looking at alternative factors, such as the hormone cortisol, which is produced in response to stress.

PROLONGED high levels can damage nerve cells in the brain and are associated with the build-up of amyloid plaques.

A recent Australian study of more than 400 people showed that those with high levels of the hormone were more likely to develop Alzheimer’s than those with low levels, suggesting that reducing cortisol might be an effective treatment.

To test this, Actinogen Medical has launched a trial of a new drug called Xanamem, which blocks the protein 11beta-HSD1 that helps make cortisol in the brain.

About 170 patients with mild Alzheimer’s symptoms will receive the drug or a placebo, and their conditions will be monitored for four months. The results are expected next year.

Targeting cortisol makes sense, says Dr Clare Walton, research manager at the Alzheimer’s Society.

‘There has been quite a lot of work on stress in the development of Alzheimer’s disease, and we see that stress and cortisol accelerate the condition,’ she says. ‘Blocking cortisol may slow Alzheimer’s progression but we don’t yet know that it will stop the disease from developing.’ Despite the disappointing progress of trials, Dr Walton feels the research into amyloid has been useful.

But she also believes a lack of funding has prevented scientists from pursuing more speculative avenues in the past.

‘Now the targets are increasing and we’re starting to see more diversification in drug development,’ she says. These new treatments are starting to come through in clinical trials, and that is really exciting.’