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Alzheimer's Susceptibility Gene?

28 April 1997 8:00 pm
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Most patients with Alzheimer's disease seem to have inherited high levels of a mutant enzyme. The finding, reported in tomorrow's issue of the Proceedings of the National Academy of Sciences, could lead to a diagnostic test for the disease.

Researchers have known for years that energy metabolism is abnormally low in the brains of Alzheimer's patients, and a prime suspect has been cytochrome oxidase (CO)--an enzyme that's a key product of a cell's energy-producing mitochondria. The enzyme is there but doesn't work correctly, suggesting that it might be mutated, says neurologist W. Davis Parker of the University of Virginia School of Medicine in Charlottesville.

A team led by Parker and Robert Davis of MitoKor, a San Diego biotech company, examined mitochondrial genes that code for three of the 13 proteins that make up the CO molecule. They focused on mitochondrial DNA because studies have shown that children of mothers with Alzheimer's are more likely to get the disease than are children of affected fathers--and mitochondrial DNA is inherited virtually only from the mother.

The team found a relatively common variant of the mitochondrial genome in which two CO genes are consistently mutated. The variant turned up in both Alzheimer's patients and normal controls, but it was three times more prevalent in the patients. The researchers transferred mitochondria from Alzheimer's patients into cultured cells that lack mitochondrial DNA. The resulting cells had impaired energy production, reflected by their high production of oxygen free radicals, damaging molecules generated when energy-generating processes don't run to completion. MitoKor is creating a diagnostic test based on the mutation assay.

The results are "by far the strongest evidence" yet that a CO defect is a primary cause of the disease, says Alzheimer's researcher Bruce Yankner of Harvard Medical School. But he points out that the work falls short of proving that CO mutations are the culprit.

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