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A Risk Test for Alzheimer's

Research with mice shows promise, but skeptics wonder if it would work on humans

THURSDAY, March 21, 2002 (HealthDayNews) -- American scientists may be on their way to developing an early warning test for Alzheimer's disease, the devastating brain disorder.

However, some experts are skeptical whether the test results, obtained only in mice so far, can be applied to humans.

Currently, there's no definitive test to determine if a person has Alzheimer's disease. The only concrete proof comes after the patient has died and an autopsy can be performed to confirm the presence of protein "plaques" in the brain.

These plaques, or build-ups of amyloid-beta protein, are the hallmarks of Alzheimer's and are thought to start forming in the brain some 10 to 20 years before symptoms show up.

In the new study, published in tomorrow's issue of Science, researchers at Washington University in St. Louis looked at 49 mice with a gene mutation that causes them to develop brain plaques. The gene defect is similar to a mutation found in some families with a strong history of Alzheimer's.

Normally, there's little amyloid-beta in the blood, mouse or human. However, when the mice were injected with an antibody called m266, amyloid-beta protein fragments flowed from the brain to the blood plasma. Within five minutes, the level of amyloid-beta in the blood plasma increased dramatically, with the amount corresponding closely to the amount of amyloid plaque build-up in the brain, according to the researchers.

They believe this antibody test could be a way to pinpoint which people have build-ups of amyloid-beta protein in the brain, and are therefore at risk of Alzheimer's. The test could also be used to measure the progression of the disease, and potentially differentiate between those who have the disease and those who have something different.

"By using the antibody in the blood, it causes more of the amyloid-beta to come out of the brain than would normally come out and, in doing that, it correlated with how many plaques there were in the brain," says Dr. David Holtzman, study's authors and associate professor of neurology at Washington University's School of Medicine. "It's sort of like a provocative test."

The test could be likened to the glucose tolerance tests given to individuals suspected of having diabetes, Holtzman says. The diabetes test causes glucose levels in the blood, which previously appeared normal, to soar.

"Obviously we don't know if we would find the same thing in humans. But if we did, it would potentially be a way to say who has developed the pathology of Alzheimer's disease," Holtzman adds. "If it really worked out well, we could predict who will develop symptoms."

The new research is actually an extension of previous published studies by the same team.

The results also corroborate that a soluble form of amyloid-beta can move from the brain to the blood, a finding demonstrated years ago, says Jorge Ghiso, associate professor of pathology and psychiatry at New York University School of Medicine.

However, the mouse models may not be a good predictor of what will work in humans, Ghiso warns. "It's possible that what you are seeing here working very well in an animal model will be totally different in the human situation," he says.

Although the biochemical composition of the lesions in the brains of the mice in the study weren't known, other experience has indicated that the amyloid-beta deposits in mouse models are different from those in humans.

The deposits in mouse models appear to be much more soluble than those in humans. Differences in solubility would significantly affect the ability of the antibody to influence the movement of amyloid-beta in humans, Ghiso says.

"These issues preclude a direct extrapolation of the present findings in laboratory animals to the actual human disease, creating skepticism regarding the use of passive administration of antibodies for diagnostic or therapeutic purposes," he says.

Even if the Washington University researchers' work leads to a workable test for humans, another question may be whether it makes sense to take a test that might predict the onset of a terrible disease for which there's currently no known treatment or cure.

Holtzman answers there are promising drugs in development that might be able to thwart Alzheimer's, and that, hopefully, predictive tests are progressing hand-in-hand with future therapies.

"If this really were a risk factor for developing cognitive trouble later, assuming we had a drug that was preventative, you would want to take it," Holtzman says. "Twenty-five years ago, we didn't know what to do to treat heart disease but now we have an armamentarium of things you can do."

What To Do: For more information on Alzheimer's disease, visit the Alzheimer's Association or the Alzheimer's Disease Education and Referral Center.

SOURCES: Interviews with David Holtzman, M.D., Charlotte and Paul Hagemann associate professor of neurology, Washington University School of Medicine, St. Louis; Jorge Ghiso, Ph.D., associate professor, pathology and psychiatry, New York University School of Medicine, New York City; March 22, 2002, Science
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