A new hope? (Image: Amelie-Benoist/BSIP/UIG via Getty Images)

DESPITE decades of work and hundreds of trials, Alzheimer’s disease remains an end-of-life trauma for millions. Could that be about to change? Although there is still no way to reverse or cure the condition, a small clinical trial in 33 people with Alzheimer’s suggests that a drug already widely used to treat rheumatoid arthritis might be able to delay or even halt its progression.

A new therapy is desperately needed. A 2012 report by the World Health Organization estimated that, by 2030, 70 million people worldwide will have dementia. The few existing treatments only ease symptoms and slow the progression of the disease, and new candidate drugs are failing clinical trials. Between 2002 and 2012, 413 trials of drugs for Alzheimer’s disease were conducted, but 99.6 per cent of them failed (Alzheimer’s Research & Therapy, doi.org/tqh).

Now, preliminary results from a pilot trial suggest that a drug used to treat arthritis could have the potential to halt the progression of Alzheimer’s.


Over six months, people with mild-to-moderate Alzheimer’s taking a placebo showed expected cognitive decline, but those taking the drug, called etanercept, had similar scores in some tests for cognitive function at the end as they did at the start of the trial.

In other tests for cognition, behaviour and coping, the symptoms of those taking the drug either stabilised or declined to a lesser degree than those of people taking a placebo.

“We saw exactly what we hoped we would, and no one has shown these effects before,” says Clive Holmes of the University of Southampton, UK, who presented the results at the Alzheimer’s Association International Conference in Copenhagen, Denmark, on Wednesday. “There’s always the proviso,” he adds, “that it must be done in larger numbers of patients in a bigger study, over a year, not six months.”

We saw exactly what we hoped we would, and no one has shown these effects before

The work is being regarded as promising by other researchers, nonetheless. “The results of this small-scale study are fascinating and exciting as they offer proof of principle,” says Robert Dantzer of the MD Anderson Cancer Center in Houston, Texas, who studies how the immune system affects illness. “Patients treated with etanercept were essentially stabilised, while the placebo-treated patients continued to deteriorate, slowly but surely.”

Patients given etanercept stabilised; those given a placebo deteriorated, slowly but surely

Etanercept works by sponging up and disposing of a protein called TNF-alpha, which ramps up and sustains inflammation following infections or as a result of metabolic or inflammatory diseases including diabetes. The drug is prescribed as a weekly injection for people with arthritis.

In 2010, Richard Chou’s team at the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, compared the health records of people with Alzheimer’s and arthritis with those of people with arthritis but not Alzheimer’s. They found that people taking anti-TNF-alpha drugs halved their risk of developing Alzheimer’s.

That might be because inflammation outside the brain has knock-on effects inside it, aggravating and accelerating dementia and brain degeneration if those processes have already begun. Earlier this year, Holmes and his colleague Hugh Perry uncovered how inflammatory molecules made by white blood cells can initiate a process that results in the death of brain cells.

“The rationale that inflammation from other diseases such as arthritis, diabetes, atherosclerosis and infections contributes to Alzheimer’s disease progression is well-founded scientifically,” says Colm Cunningham of Trinity College Dublin in Ireland, who helped Perry piece together the mechanism by which inflammation elsewhere in the body affects disease in the brain. Tackling some of these conditions could help fend off Alzheimer’s (see “Protect yourself“).

Of the 33 people with mild-to-moderate Alzheimer’s disease participating in Holmes’s trial, 18 received weekly injections of etanercept, while 15 were given a placebo of weekly saltwater injections, for six months. At the start, middle and end of the trial, a host of tests of the participants’ cognition, behaviour and well-being were carried out by assessors unaware of which volunteers had received treatment.

The main objective of the small study was to check that the treatment was safe and well-tolerated by people with Alzheimer’s disease. But Holmes’s team found that the participants taking etanercept performed comparatively better on memory, behaviour and well-being tests, although there was no statistically significant difference in their performance on other tests of cognition and depression (see “A measured effect“).

In a small pilot study like this, the success of the drug could be down to chance, says Holmes. “But the results are very consistent, and the big Alzheimer’s trials that have been performed on thousands of patients have not shown anything like it.”

Other researchers warn that doing larger studies is paramount before people get excited about etanercept’s potential. “Trials like this are not big enough to tell whether the drug works, but rather to check the drug is safe, and it is,” says John Hardy of University College London. “Analysing the data suggests there may have been an improvement, but the study is about a tenth the size we would need to draw a conclusion about whether the drug slows disease progression.”

Holmes says expanding to larger trials would be relatively simple because the drug has a proven track record. “We know a lot about it, and it’s already out there for arthritis,” he says. “It could move very quickly, and within maybe two to three years we would be there.”

“It’s certainly worth following up with a larger study,” says Eric Karran, director of research at the charity Alzheimer’s Research UK. “Considering the small size of the trial, it’s very promising to see positive effects on measures of memory and thinking, behaviour and day-to-day activities, and for these to get stronger with time.”

Protect yourself Forty-four million people are estimated to have Alzheimer’s disease, and there is currently no way to halt or reverse its ravages on the brain (see main story). But a third of those cases could have been prevented by lifestyle changes, says neuroscientist Carol Brayne at the University of Cambridge. Alzheimer’s is caused by a combination of genetics and lifestyle factors. To work out the effect of potentially modifiable influences, Brayne’s team reanalysed previous studies. These covered seven factors known to be associated with Alzheimer’s: diabetes, depression, physical inactivity, smoking, low educational attainment, obesity and high blood pressure in middle age. They then factored in associations between some of the factors. For example, increasing physical activity can also lower blood pressure. One in three cases of Alzheimer’s can be attributed to modifiable factors, estimate the researchers. By reducing the relative risk from each of these factors by 10 per cent every decade, it would be possible to reduce the 2050 prevalence of Alzheimer’s by 8.3 per cent, and prevent 9.6 million cases. That is a win-win situation, says Brayne. Tackling factors such as physical inactivity will lead to a healthier old age in general as well as reducing the risk of developing Alzheimer’s (The Lancet Neurology, doi.org/tqj). Helen Thomson

A measured effect Thirty three people took part in six-month pilot trial of a drug called etanercept for Alzheimer’s disease. Clive Holmes at the University of Southampton, UK, and his colleagues used a host of tests to measure the mental faculties of the participants. Some of the tests seem to show that etanercept reduces mental decline. COGNITION The Mini-Mental State Examination can evaluate memory problems, and is scored from 30 (completely healthy) to 0 (completely incapable). At the start of the trial, participants had an average score of 20. Six months later, the score had barely changed in those taking the drug. The scores of people taking a placebo dropped by two points on average. In another cognitive test, those taking the drug showed less of a decline than those taking the placebo, but the difference was not statistically significant. COPING ABILITIES The Bristol Activities of Daily Living Scale measures how well a person can feed, wash and look after themselves. In this test, higher scores signal greater disease severity. Participants taking a placebo saw their scores increase by, on average, 5.2 points more than those taking etanercept. In another test of the severity of mental illness, however, the difference between the two groups was not significant. BEHAVIOUR The Neuropsychiatric Inventory assesses people on a range of things including delusions, anxiety and apathy. On the 144-point scale, in which 0 signifies the best health, the scores of people taking a placebo increased by an average of 10.5 points above those of the participants taking etanercept. However, another test for depression showed no significant difference between the two groups.

This article appeared in print under the headline “Drug stalls attack of Alzheimer’s”

When this article was first published it confused the number of patients in the treatment group with that in the control group