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Third Public Conference: Cellular Aging
and Apoptosis The Genetic Basis for Neurodegeneration
in Alzheimer's Disease Speaker Alzheimer's disease (AD) is the most common cause of dementia in elderly people, and Dr. Tanzi has been instrumental in discovering genes that account for nearly half of early-onset familial Alzheimer's disease (FAD). In addition to analyzing the harm these genes do in early-onset FAD, he and his colleagues are also exploring the complex genetic underpinnings of the more common, late-onset form of Alzheimer's. Dr. Tanzi is Director of the Genetics and Aging Unit in the Department of Neurology at Massachusetts General Hospital, as well as Professor of Neurology and Neuroscience at Harvard Medical School. He received his B.S. in microbiology and history from the University of Rochester and his Ph.D. in Neurobiology from Harvard University. Dr. Tanzi has received numerous honors, including the Metropolitan Life Award for Medical Research and the Potamkin Prize. Topic Dr. Tanzi made history in 1987 with the discovery of the amyloid-beta precursor gene, the first genetic cause of familial Alzheimer's disease. He later played an important role in the discovery of two other important genes for early-onset FAD, called Presenilin 1 and 2, and since then his lab has been investigating how these gene defects cause neurodegeneration in AD, including their roles in apoptosis and oxidative stress. In addition, Dr. Tanzi has been seeking genetic risk factors for the more common, late-onset form of AD. Toward this end, he and colleagues at the National Institutes of Health carried out a high-resolution genome screen of more than 400 families. Prior to this screen, the only known risk factor for late-onset AD was APOE4, one of three alleles for a gene that directs production of apolipoprotein E. People with two copies of the APOE4 polymorphism are at especially high risk for developing AD; people with one copy are at somewhat elevated risk. The genome-wide screen turned up another, unrelated polymorphism that may pack the same wallop as a double dose of APOE4. This is A2M-2, an allele of the gene for alpha2 macroglobulin (A2M). The A2M-2 variant is carried by about 30% of the U.S. population, and Dr. Tanzi and his colleagues estimate that people with this allele are three times more likely to develop late-onset AD than those with standard A2M. The researchers are now trying to discover whether the FAD mutations
and the polymorphisms linked to late-onset AD might, in the final analysis,
use the same basic strategies to cause disease. One promising hypothesis
is that they may alter the cell's ability to handle calcium, and that
this in turn may promote the formation of damaging amyloid-beta plaques.
If confirmed, this could pave the way to new therapeutic approaches.
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