Interrupted Alzheimer's Vaccine Study Yields Hopeful Results

Alzheimer's Disease and Vaccine

Newly published results from prematurely stopped study suggest mental, physical effects from immune system attack on key Alzheimer's protein

Training the body's immune system to fight back against Alzheimer's disease may still offer a promising option for slowing or even preventing the tragic brain disorder that affects 4.5 million Americans.

That's the conclusion of two new papers published in the journal Neurology by an international team of researchers who vaccinated hundreds of Alzheimer's disease patients with beta amyloid, a protein that builds up in Alzheimer's-affected brains.

The study was stopped early in 2002 after a few participants developed brain inflammation. But the researchers continued to monitor the patients for up to a year after their last injection. The new papers, including one led by the University of Michigan Health System neurologist who headed the study's safety committee, summarize the results of that effort.

Even as those results are published, doctors at U-M are preparing to recruit participants for a phase II clinical trial to test a new Alzheimer's immunotherapy vaccine strategy that has been through a phase I safety trial. The phase II study, which aims to stimulate an immune attack against beta amyloid without raising brain inflammation risk, is being conducted at 30 centers in the United States and dosing has already begun at some sites. All the trials have been funded by Elan Corporation and Wyeth Pharmaceuticals.

Results from the interrupted trial show that on the whole, study participants whose immune systems mounted a response against beta amyloid performed significantly better on a series of memory tests than those who received a placebo injection.

Brain scans also showed that patients who had an immune response experienced a decrease in brain size, possibly indicating the removal of built-up protein due to an immune system attack. A smaller group of immune responders also had a decrease in levels of a protein called tau in their spinal fluid, compared with participants who received placebo, possibly indicating a slowing in the death rate of their brain cells.

"The idea of inducing the immune system to view beta amyloid as a foreign protein, and to attack it, holds great promise," says Sid Gilman, M.D., F.R.C.P., the first author on one of the new papers and the head of the Data Safety Monitoring Board for both clinical trials. "We now need to see whether we can create an immune response safely and in a way that slows the progression of Alzheimer's disease and preserves cognition."

Gilman is the William Herdman Professor of Neurology at the U-M Medical School and director of the Michigan Alzheimer's Disease Research Center, one of 32 in the country funded by the National Institute on Aging.

Nancy Barbas, M.D., M.S.W., a U-M neurologist who will soon begin recruiting participants for the new trial, calls the approach, known as immunotherapy, exciting. "Safety is paramount, given the experience with the last trial, and the new study is designed to be extraordinarily cautious and conservative," she says. "But if we can show an effect, it will mean we're that much closer to giving patients and their families better options for treatment."

Rather than injecting participants with beta amyloid itself, the new trial is based on injections of humanized antibodies against part of the beta amyloid molecule. The antibodies should help trigger the immune system to attack beta amyloid, but will be cleared by the body soon after injection. That means a series of six injections to "remind" the body to attack beta amyloid.

As in the previous study, participants will be randomly assigned to receive either antibodies or a placebo; neither they nor the researchers will know what they got until the 27-month study ends. The new study will enroll 180 adults between the ages of 50 and 85 who have a diagnosis of probable Alzheimer's and a caregiver who can bring them to frequent appointments for brain imaging, neuropsychological testing and blood tests. Some participants will have additional blood tests or spinal fluid tests; they will also have a slightly higher chance of getting antibodies.

Gilman explains that the concept of vaccinating against beta amyloid was first proposed by scientist Dale Schenk. In the late 1990s, Schenk and his colleagues showed that vaccination from birth could prevent mental decline in mice that had been bred to develop Alzheimer's-like disease. They and others also showed that older mice receiving the vaccine appeared to regain cognitive function.