Scientists inch towards answers on how dementia works

On the face of it, dementia research may seem in a grim position with drug after drug failing clinical trials, and the ultimate cause of Alzheimer’s and related diseases remaining as elusive as ever.

We still lack medicines that can even slow the development of dementia, let alone stop or reverse it, yet David Reynolds, who follows the field closely from his position as chief scientist with the charity Alzheimer’s Research UK, sounds optimistic.

“We are getting an increasingly sophisticated understanding of what is going on in these diseases,” he says. “We are starting to use the information to develop new treatments.”

The most obvious feature of Alzheimer’s is that nasty misshapen proteins build up in the brain, while the organ itself shrinks as its neurons die off. At the same time the patient’s cognitive abilities gradually decline, with progressive memory loss, confusion and personality change. Scientists are now trying to disentangle the complex web of cause and effect that gives rise to Alzheimer’s and, with different biochemistry, to other forms of dementia.

Two proteins in particular accumulate in Alzheimer’s brains: “amyloid plaques” and “tau tangles”. Amyloid plaques have received by far the most attention from scientists and drug developers. These sticky deposits are the endpoint of a biological process that begins with a molecule called amyloid precursor protein (APP) which is present in all healthy neurons.

The so-called amyloid pathway involves enzymes that cut APP into fragments called amyloid beta or aBeta, which accumulate into insoluble plaques.

Although the amyloid pathway is widely considered to be a hallmark of Alzheimer’s, it does not lead inevitably to dementia. The 90+ Study at the University of California, Irvine, has enrolled 1,600 people over the age of 90, who have agreed to undergo cognitive assessment while alive and then to donate their brain for analysis after they die. Roughly one-third of participants have dementia, one-third have some cognitive loss and one-third “retain excellent cognition and motor skills”, says Claudia Kawas, the 90+ Study leader.

“When we did autopsies on the brains of our non-demented individuals, we found that 40 per cent had fully fledged Alzheimer’s disease pathology,” she adds. In other words many very old people have a brain full of plaques and tangles, without suffering dementia. Conversely one-third of over-90s with dementia have not accumulated amyloid or tau but are suffering from severe loss of cells in the part of the brain called the hippocampus.

The key genetic determinant of whether amyloid accumulation causes Alzheimer’s is a gene called ApoE that produces proteins involved in fat metabolism. One common variant called ApoE-2 protects against dementia even in people whose brain is full of amyloid, says Prof Kawas, whereas those with the ApoE-4 gene are almost certain to develop dementia as amyloid plaques form.

One of the hottest topics in dementia research is the immune system. Evidence is accumulating that inflammation associated with an unbalanced immune response contributes to Alzheimer’s. The latest study, published last month by researchers at Southampton and Oxford universities, concluded that people who took anti-inflammatory medication for arthritis cut their risk of developing dementia by half.

The UK Alzheimer’s Society is funding a controlled clinical trial of anti-inflammatory arthritis drugs called TNF-alpha inhibitors.

“It is vital to explore whether drugs developed for other conditions also have benefits for dementia, as it could make it much quicker to get new drugs to the people who desperately need them,” says James Pickett, Alzheimer’s Society head of research.

The longer term aim is to design medicines that modulate the immune system specifically to fight against dementia. Microglia, the brain’s specialist immune cells, will be key.

Alongside the development of dementia treatments, researchers are working on better diagnostic tests, which could eventually find a place in medical practice.

One of the hottest topics in dementia research is the immune system

The best available indicator of Alzheimer’s pathology is still the build-up of aBeta protein in the brain while the amyloid plaques are still being formed. The molecules most toxic to brain cells seem to be so-called oligomers that form when aBeta molecules link together rather than the end-stage plaques.

A promising approach to drug development is to stop these aBeta oligomers forming in the first place.

The only techniques available now to track this activity are PET brain scans (expensive) and cerebrospinal fluid testing (invasive).

But the long-awaited prospect of a blood test for amyloid formation came closer last month when a team of Japanese scientists published a study that showed they had been able to identify individuals with abnormal aBeta deposits in the brain with 90 per cent accuracy.

“These data are very promising and may be incredibly useful in the future,” says Professor Tara Spires-Jones, a dementia specialist at Edinburgh University. Since 2012 a widely accepted target has been to have the first treatment that safely modifies the underlying course of Alzheimer’s available by 2025.

That is still achievable, says Dr Reynolds, though the slow pace of clinical development means that this drug must already be in at least the early stages of testing in patients.

It will not be a miracle cure — and it may need to be combined with other drugs — but once it has proved its efficacy, this pioneering product will provide a basis for a real pharmaceutical assault on dementia.