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Alzheimer's Vaccine Research Back On Track

Memory test improvements suggest the therapy may have a future

MONDAY, May 9, 2005 (HealthDay News) -- The idea of a vaccine against Alzheimer's disease may yet have some life left to it.

Researchers at the University of Michigan have started a new, albeit modified, trial, even while the May 10 issue of Neurology publishes follow-up data to an Alzheimer's vaccine trial that was halted due to safety concerns in 2002.

The earlier trial was halted after about 6 percent of participants developed a dangerous brain inflammation, encephalitis. However, researchers continued to monitor the remaining patients for up to a year after their last injection -- with some encouraging results.

Participants whose immune systems had mounted a high antibody response to beta-amyloid levels in the brain performed better on memory tests than people who had received a placebo, the Michigan team reported.

They also experienced an unexpected decrease in brain size, perhaps linked to clearance of disease-causing proteins from the brain.

"It's really the publication of what was presented at the Alzheimer's Association meeting in July of last year," said Dr. Sam Gandy, vice president of the Alzheimer's Association's Medical and Scientific Advisory Council.

"The trend is in the right direction. There were some statistically significant improvements on some neuropsychological measures, but they were not obviously meaningful at the bedside," he said.

All of this work, including the new trial, are based on the so-called 'amyloid theory' of Alzheimer's disease, which hypothesizes that rising levels of beta-amyloid protein deposited in the brain are at the root of the disease.

"It's a very popular hypothesis, and the only way to prove whether it's right or wrong is to develop an effective anti-amyloid strategy, expunge amyloid from the brain and see if people never get Alzheimer's or get better," Gandy said.

So far, the evidence has remained unclear.

In the halted trial, about 20 percent (59) of the 300 participants who received at least one injection developed significant quantities of antibodies against beta amyloid in their blood.

In general, those who developed antibodies also displayed stabilization of memory and scored better on certain neuropsychological tests evaluating memory than the placebo group. Furthermore, among those patients who did develop antibodies, those who produced relatively high levels achieved better results on memory tests than those who developed lower levels.

"There was a dose response," said Dr. Sid Gilman, director of the Michigan Alzheimer's Disease Research Center in Ann Arbor and head of the Data Safety Monitoring Board for both trials being reported in Neurology. The trials are funded by two drug makers, Elan Corp. and Wyeth Pharmaceuticals.

Compared to those receiving a placebo, patients who developed antibodies also experienced a decline in levels of tau protein in the cerebrospinal fluid. Tau proteins have long been associated with brain cell death in Alzheimer's patients.

"That suggests that fewer brain cells died in people who achieved a good antibody titer," Gilman said.

The second paper delivered somewhat of a surprise: The authors had anticipated that patients who had a good antibody response and good memory stabilization would have less brain shrinkage than patients unresponsive to the immune-based therapy. In fact, they experienced brain shrinkage above and beyond that of unresponsive individuals.

Gilman's interprets that finding to mean that vaccine-stimulated antibodies removed not only the beta amyloid deposited within the brain, but also the soluble beta amyloid bathing the brain. "The beta amyloid protein bathing the brain may be causing the damage by injuring nerve cell connections or synapses," he speculated.

The new trial is trying to incorporate seemingly successful elements of the old trial without the safety hazards. More encouragement arrived from autopsies that showed that participants who died of causes other than encephalitis seemed to have successfully cleared some beta amyloid from their brain.

"You could speculate that's because the antibody was effective. On one side that's good," Gandy said. "On the other side, you can also say, 'Well if you've got rid of amyloid and they didn't get any better, are you going down the right path?"

In the hopes of eliminating previous problems, researchers are injecting participants with already prepared antibodies, instead of beta amyloid itself, a method called passive immunization -- as opposed to active immunization, where doctors try and spur the body to create antibodies on its own.

One drawback to the passive approach is that participants have to come back for repeat immunizations. With the active vaccine, they would need far fewer injections, explained Gilman, who is also chairman of the Data Safety Monitoring Board for these ongoing trials.

"The good thing is if there are any side effects, infusions can be immediately stopped. The problem with the vaccine is once you put it in the skin and muscle, you can't get it back out," Gandy said. "There's no way to predict whether it will be dramatically more effective."

Administration of the passive immunizations has only just begun, so results should be years away, a frustratingly slow pace for the millions of patients and families living in the clutch of Alzheimer's.

"This is a very slow process, and the disease itself moves very slowly so everything you're going to test is going to take months to a year," Gandy said. "It's a desperate disease, families are desperate, there's a visible area of inquiry so everyone hears about every single step. This is what drug discovery has gone through for everything we have. This is how we're going to get at the next generation of treatment."

More information

Learn more about Alzheimer's at the Alzheimer's Association.

SOURCES: Sid Gilman, M.D., FRCP, William Herdman Professor of Neurology, University of Michigan Medical School, and director, Michigan Alzheimer's Disease Research Center, Ann Arbor; Sam Gandy, M.D., Ph.D., vice president, Medical and Scientific Advisory Council, Alzheimer's Association, and director, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia; May 10, 2005, Neurology
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