New Alzheimer's-Associated Mutation May Provide Key To Disea...( Researchers from the Massachusetts Ge...)

Researchers from the Massachusetts General Hospital (MGH) and colleagues at the Harvard School of Public Health (HSPH) and other institutions have identified a new gene mutation strongly associated with the risk of developing late-onset Alzheimer's disease, the most common form of the brain disorder. Most significantly, the protein coded for by this gene -- known as alpha-2 macroglobulin (A2M) -- interacts with proteins coded by other Alzheimer's-associated genes, suggesting a process that could be key in the disease's development.

"This finding leads us directly to a protein pathway that we think drives the Alzheimer's disease process," says Rudolph Tanzi, PhD, director of the MGH Genetics and Aging Unit and senior author of the report, appearing in the August issue of Nature Genetics. "It could be a powerful new target for the development of drugs to prevent or treat this disease." Tanzi and his colleagues stress that the new mutation is not appropriate for use in diagnosing or predicting Alzheimer's disease. The data also are being presented July 22 in Amsterdam at the Sixth International Conference on Alzheimer's Disease and Related Disorders.

Steven Moldin, PhD, acting chief of the NIMH Genetics Research Branch says, "If replicated, this would prove to be a very major finding in understanding the genetic basis of the common, late-onset form of Alzheimer's disease."

Scientists have long been familiar with the A2M protein and its gene, found on chromo-some 12. A2M is a protease inhibitor, controlling the activity of enzymes that break down other proteins, and has been known to interact with a nerve cell receptor called LRP (low-density lipoprotein receptor-related protein). Two important clues led Tanzi and his colleagues to examine whether mutations in A2M might be associated with Alzheimer's risk. First, two proteins known to be involved with Alzheimer's -- the amyloid precursor protein and apoE -- also interact with LRP. Second, cell culture
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Contact: Susan McGreevey
smcgreevey@partners.org
617-724-2764
Massachusetts General Hospital
22-Jul-1998