Alzheimer's Research Brings Progress, Setbacks

By Steven Reinberg
19 july 2008-- It's one step forward, one step back in the search for treatments against Alzheimer's disease.
In one of two studies in the July 19 issue of The Lancet, an older drug called dimebon significantly improved Alzheimer's symptoms. But in a second report, a once-promising vaccine failed to prevent the progression of Alzheimer's -- even though it cleared dementia-linked amyloid plaques in the brain.
This week's issue of the journal is devoted to research into the causes and treatment of dementia, including Alzheimers disease. According to the U.S. National Institutes of Health, an estimated 4.5 million Americans have Alzheimer's disease, which is thought to affect one in 20 people between the ages of 65 and 74. The estimated rate goes up to nearly half of those aged 85 and older.
In one study, British researchers led by Dr. Clive Holmes, from the Memory Assessment and Research Centre at Moorgreen Hospital in Southampton, analyzed data on 80 Alzheimer's patients who were treated with an experimental vaccine that for now is dubbed AN1792.
The vaccine is targeted at the removal of amyloid protein plaques that clump around brain cells in increasing numbers as Alzheimer's progresses. The theory was that dementia could be slowed or reversed once the plaques were cleared, and experiments in animals have shown that removing these plaques improves brain function.
Indeed, long-term follow-up of Alzheimer's patients treated with AN1792 did show, "a reduction in the number of plaques in the brains of patients -- in some cases there was a virtually complete removal of plaques," Holmes said.
But there was a catch. "Crucially, there was no evidence that the patients benefited by the removal of plaques and even those subjects with virtually complete removal continued to deteriorate and had severe end-stage dementia prior to their death," Holmes said.
Based on these results, the researcher now believes that removing plaques -- at least by this method -- is unlikely to make a significant difference to the clinical outcome of patients with established Alzheimer's disease. "In addition, it strongly suggests that plaques are not sufficient on their own to account for disease progression," Holmes said.
Based on the findings, novel strategies for the treatment of Alzheimer's disease should not focus on the removal of plaques in patients with established Alzheimer's, Holmes contends. "Treatments should move towards preventing plaques from building up in the first place," he said. "Or in established Alzheimer's disease, treatments should focus more on non-plaque therapies."
Dr. Sam Gandy, chairman of the Alzheimer's Association's National Medical and Scientific Advisory Council, said the new finding suggests that other forces besides plaque build-up are driving disease progression.
"If you don't start with your vaccine until you are at a later stage of disease and other processes are already established, the horse may be already out of the barn," Gandy said. "It is possible that amyloid is like a match lighting a fire and once the fire is out of control, dealing with the match isn't that effective."
But there was better news in a second study. In that work, Dr. Rachelle S. Doody, a professor of neurology at the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine in Houston, and her colleagues studied the effects of the drug dimebon on 183 patients in Russia with mild to moderate Alzheimer's disease. The drug is currently not marketed anywhere, and was previously used in Russia as an antihistamine.
"This is a medication that has not previously been studied in Alzheimer's disease," Doody said. In the trial, patients were randomly assigned to 20 milligrams of dimebon three times a day, or a placebo.
After six months, Doody's team found that patients on dimebon had significant improvement in cognitive ability, compared with those receiving placebo.
"We found treated patients were improved in their thinking abilities, their behavioral symptoms [and] their daily skills abilities, compared to people who took placebo," she said.
The patients were evaluated using ADAS-cog, a battery of tests that assesses a person's ability to track dates, comprehend instructions, follow commands, memorize word lists, and complete simple tasks such as copying drawings or addressing an envelope.
At six months, patients receiving dimebon showed an improvement of 1.9 points on the ADAS-cog scale from the beginning of the study, while those on placebo continued to decline. After a year, those receiving dimebon showed a 6.9 point increase on the ADAS-cog scale, the researchers report.
"This first trial was promising," Doody said. "This is not a cure for Alzheimer's disease, but the benefits could last for a long time. The drug appears to slow the clinical progression of the disease."
The study was done in Russia because dimebon had been approved there as an antihistamine. Dimebon is made by the San Francisco-based biopharmaceutical company Medivation. Doody is on the Scientific and Clinical Advisory Board of Medivation and has stock options in the company.
Another phase III trial has just started, Doody said. This six-month trial is being conducted in the United States, Europe and South America and is now in the process of recruiting several hundred patients, she noted.
"We are anxiously awaiting the completion of the next study, so that we can see if this drug could potentially be approved for treating Alzheimer's patients," Doody said.
Gandy said the drug does appear to be superior to the currently approved medicines for Alzheimer's.
"This is the first new promising symptomatic therapy in a long time," Gandy said. "This drug could potentially add to the effects of other drugs such as Aricept, Namenda and Exelon," he said. "I think it's a pretty exciting development."