PHILADELPHIA – The brains of some of the people who received an experimental vaccine against Alzheimer’s disease have shrunk, but scientists don’t know whether that is an ominous sign that a promising therapy has failed or an indication the drug may be halting the advance of the disease.

The trial, which began nearly three years ago when 360 Alzheimer’s patients received a vaccine designed to stimulate their immune system to attack a protein that clumps in the brain, was stopped in February 2002 when 15 of the patients developed serious inflammation in the brain.

On Wednesday, scientists with Elan Corp., the Irish firm that developed the vaccine, presented research from brain scans showing atrophy in some of the patients, including in the hippocampus, a brain region involved in memory. In general, brain atrophy is considered a sign that brain cells are dying.

In total, the brains of a group of patients who responded to the vaccine shrank about 3 percent, compared with 2 percent in a placebo group, according to research presented at the 9th International Conference on Alzheimer’s Disease and Related Disorders of the Alzheimer’s Association.

One possible explanation is that beta-amyloid, the protein that many feel causes Alzheimer’s, was being cleared from the brain. “There could be all sorts of reasons behind it (the brain shrinkage),” said Dale Schenk, Elan’s chief scientific officer. “It’s not necessarily a bad thing and it could be a good thing.”

Elan also presented research suggesting that patients who developed the desired immune response to the vaccine and whose brains shrunk actually were doing better on some cognitive tests than those who did not develop a response.

However, on other assessments of how the patients were doing, there was no benefit.

In addition, autopsies on four patients in the trial who died of causes that were not believed to be related to the vaccine showed that substantial amounts of beta-amyloid had been cleared from their brains.

Still, other researchers said the brain atrophy was not a good sign and also expressed frustration with the lack of data on how all the patients in the trial were doing.

“They’ve got 350 patients,” said Peter Davies, a professor in the department of pathology and neuroscience at Albert Einstein College of Medicine. “What happened to all of them? Where is the data? It’s dribbling out in bits and pieces.”

He said brain atrophy usually means a loss of cells. Davies noted some scientists, including himself, don’t believe that beta-amyloid is the real culprit in Alzheimer’s disease.

He added, “If the patients did worse and there was atrophy, then I’m very concerned.”

At the same time, it is possible that brain shrinkage is not a good measure for assessing the effects of new treatments, said Eric Siemers, a physician and medical adviser to Eli Lilly & Co., who presented research on a different drug designed to prevent beta-amyloid from forming in the brain.

“It just may be a little more complicated than we thought,” Siemers said.

Sam Gandy, an Alzheimer’s researcher at Thomas Jefferson University, said it is possible that the vaccine caused brain cells to die, resulting in the brain shrinkage.

“It is not what you would expect to be a good outcome,” he said.

He said the results suggest that more animal research is needed to see if the brain shrinkage can be explained by the reduction of beta-amyloid.

However, Michael Weiner, chairman of the neuroimaging working group of the Alzheimer’s Association and a professor of medicine at the University of California, San Francisco, said he was encouraged by the fact that the patients who had the biggest response to the vaccine seemed to do better on some neuropsychological tests.

“I think the glass is half full,” he said. “Immunotherapy is alive and kicking.”

In either case, Elan now is concentrating on a so-called passive vaccine, which should cause fewer problems with swelling the brain. That trial, which involves a smaller number of patients, began last year.

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AP-NY-07-21-04 1937EDT

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