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Experiment finds hope in vaccine for Alzheimer's

By Alice Dembner, Globe Staff, 5/22/2003

n experimental vaccine has slowed mental decline in some patients with Alzheimer's disease, researchers reported today, offering the first evidence that an inoculation can stem the progression of the delibitating disease that afflicts 4 million Americans.

The preliminary findings on 30 people suffering from Alzheimer's are part of a much larger experiment that was halted 18 months ago when some patients suffered potentially fatal brain inflammation. Today's positive results provide new impetus to scientists seeking a safer vaccine.

Eighty percent of the patients inoculated responded to the vaccine. One year after receiving the inoculation, only 16 percent of those patients had deteriorated from mild or moderate dementia to severe dementia, compared with 67 percent of those who received a placebo or did not respond to the vaccine, according to the results reported in today's issue of the journal Neuron.

''This study gives us hope,'' said Zaven Khachaturian, a senior science adviser to the Alzheimer's Association who reviewed the research. ''The path ahead is tortuous and difficult, but we think we have another avenue to attack the disease.''

The study by doctors from the University of Zurich also supports the prevailing scientific theory that sticky brain deposits called beta-amyloid plaques cause Alzheimer's. The vaccine is intended to slow plaque buildup that can cause rapid mental decline.

Currently, the only approved Alzheimer's treatments are drugs that ease some symptoms, but don't stop the disease. In a separate study, reported in today's issue of Nature, scientists found that lithium helped to fight plaque formation in lab mice.

Dr. Roger M. Nitsch, senior author of the Zurich study, said the results showed promise, but he warned about side effects.

''If confirmed in a larger population of patients, our findings will help to develop vaccination against beta-amyloid for the treatment and the prevention of Alzheimer's disease,'' Nitsch said in an e-mail interview.

But he said, ''The safety and tolerability of the vaccine . . . needs to be improved significantly.''

Several companies are developing potential Alzheimer's vaccines, but so far only a product jointly made by Elan Corp. of Ireland and Wyeth of New Jersey has been tested in humans. The drug trial involved a total of 300 people with mild to moderate Alzheimer's at 28 sites worldwide. Each participant received two doses of either vaccine or placebo.

Today's report on 30 patients is the first data published on the vaccine's effectiveness. A report on all patients in the vaccine program is expected later this year.

The vaccine, which contains beta-amyloid, is intended to train the patient's immune system to recognize the plaques and create antibodies to attack them. Scientists hoped it would delay or reverse the disease.

The companies stopped giving the vaccine in January 2002, after 18 participants suffered brain inflammation, but doctors continued to monitor the patients for another year. Two of those with brain inflammation subsequently died. Those side effects dashed hopes for a breakthrough and set up a significant hurdle for approval of any Alzheimer's vaccine by the Food and Drug Administration.

Of the 30 patients in the Zurich group covered in the Neuron report, 24 received the vaccine, and 20 responded by producing antibodies. The greater the immune response to the vaccine, the less the patients' cognitive abilities declined, according to the report.

On one measure of mental performance -- which tests language, attention, and the ability to follow simple commands -- two-thirds of the patients who responded to the vaccine held their ground, compared with only 22 percent of the others. Similar results were reported for a memory test.

The stabilization of the patients' condition was also seen in their daily lives. Scientists interviewed the patients' caregivers and found that patients who generated antibodies to the vaccine showed far less decline in their ability to feed and bathe themselves, to shop, and pay bills. Despite the study's small numbers, the differences between the two groups were great enough to give the study statistical validity.

Three patients in the group suffered brain inflammation, but even so, the two who made antibodies maintained their cognitive function over the course of the year. The third declined.

The results are expected to draw more companies into work on a vaccine. Elan hopes to begin testing two new vaccines on patients by year's end, according to Dale Schenk, senior vice president for discovery research.

At least two other companies, Eli Lilly and Mindset Pharmaceuticals, are actively working on a vaccine, and researchers say that many others have been waiting for the kind of proof-of-concept that the Zurich results provide.

To prevent the drastic reactions seen in some study patients, researchers are testing different vaccine formulations. One version uses a smaller portion of the beta-amyloid protein, and another injects antibodies made in the lab, rather than triggering the body to make antibodies itself.

''The possibility that we might be able to remove plaques from the brain appears to be a real one,'' said Schenk. ''Their results are quite encouraging, but it is only 1 of 28 sites involved in the study. We're still reviewing the rest, and we're trying to be very, very cautious in the interpretation of the data.''

In addition, the entire study ''wasn't designed to test fully for efficacy,'' he said. ''The numbers weren't large enough for that.''

Khachaturian, a former director of Alzheimer's research at the National Institutes of Health, said the new results are significant because they are the first to show that ''if you eliminate or reduce the amyloid formation, you also delay the progression of the disease.''

Many questions remain, he said, including why only some of those who received the vaccine apparently benefited, whether the side effects can be avoided, and what the long-term effects will be.

''But the viability of the vaccine approach has regained some of the momentum that it lost with the stopping of the trial,'' Khachaturian said. ''The chance of it working looks a lot brighter than it did months ago.''

Alice Dembner can be reached at Dembner@globe.com.

This story ran on page A1 of the Boston Globe on 5/22/2003.
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