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Elevated levels of a peptide in the blood of still-healthy adults may signal an increased risk of developing Alzheimer's disease, according to new research by Dr. Richard Mayeux and his colleagues in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain. The findings suggest that people at high risk could be given prophylactic therapies to reduce levels of the peptide, AB42, and prevent or delay the onset of the disease. It is projected that the number of Alzheimer's patients in the United States will triple by 2050. The research was published in the Nov. 11 issue of Neurology.

By the time symptoms of Alzheimer's disease are detectable, 10 to 20 years have passed since the disease began attacking and killing neurons in the brain. Once symptoms appear, most researchers believe it is probably too late to stop the progression of the disease. Therefore, therapies that prevent the disease from ever reaching this point are considered a better strategy. But preventive therapies can succeed only if doctors are able to predict who is at high risk for developing the disease years in the future. Currently, the only known risk factor for the vast majority of patients is the presence of the APOE4 allele, which quadruples the risk. Since people without the allele also develop the disease, more risk factors will have to be found before it is possible to more accurately assess risk.

"The situation is analogous to high cholesterol for heart attacks," says Dr. Mayeux, co-director of the Taub Institute and the Gertrude H. Sergievsky Professor of Neurology, Psychiatry, and Epidemiology. "Having high cholesterol doesn't mean you'll definitely have a heart attack, but it does mean you're at a higher risk for one."

In the new study, the researchers measured levels of amyloid beta-peptide, or AB42, in 530 people over age 65 and followed their progress for five years. High levels of AB42 more than doubled the risk of Alzheimer's for the study's participants, as compared with participants who had the lowest levels of the peptide. Dr. Mayeux cautions that the AB42 levels of more people need to be followed through time to more definitively tag high AB42 as a risk factor. But Dr. Mayeux believes the results are promising.

Because it appears that AB42 can move between the blood plasma and the brain, thus contributing to plaque formation, AB42 may also be a prime target for preventive drugs. "Reducing plasma levels of the peptide may lower the risk of developing the disease, just as cholesterol-lowering drugs reduce the risk of heart attack and stroke," Dr. Mayeux says.

Several groups of researchers including Dr. Shi Du Yan, associate professor of clinical pathology, are working on developing compounds that would soak up plasma AB42 or prevent plasma AB42 from adding to plaques in the brain. Dr. Yan's work focuses on the RAGE receptor, which can shuttle plasma AB42 into the brain, and trying to find ways in which the receptor might be blocked. Her most recent results show that Alzheimer's model mice that overexpress an AB42 precursor produce smaller brain plaques when a soluble form of the receptor injected into the mice binds plasma AB42 and prevents it from moving into the brain. This study was reported in July 2003 issue of Nature Medicine.

There is little debate among neuro-scientists that the accumulation of AB42 is an early and important event in the development of Alzheimer's disease. Dr. Michael Shelanski, co-director of the Taub Institute with Dr. Mayeux and professor and chairman of pathology, has found evidence that AB42 causes dysfunction in neurons long before they die.

"An early intervention that limits the effects of AB42 at the cellular level might lead to a method to prevent Alzheimer's disease altogether, but we need to know who to treat," Dr. Mayeux says.

The research was supported by the National Institute on Aging, the Charles S. Robertson Memorial Gift for Research on Alzheimer's Disease from the Banbury Fund, Blanchette Hooker Rockefeller Fund, the Education Foundation, and the Taub Foundation.

—Susan Conova


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