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Research Finding Indicates Genetic Defect Is Major Factor

March 12, 1987

WASHINGTON (AP) _ People with Alzheimer’s disease have abnormal numbers of the gene responsible for a brain-crippling protein associated with the condition, a finding scientists say is strong evidence that a genetic defect is a major factor in the disease.

American and French researchers said Thursday they also found the same abnormal gene duplication in patients with Down’s syndrome, a discovery that may explain the long-suspected link between the two conditions.

Extra copies of this gene, which is present in everyone, could force the body to make abnormal amounts of the protein. This excess accumulation could be a critical factor in the pathology seen in both diseases, scientists said.

The findings are the latest in a recent series of advances concerning Alzheimer’s disease, including discovery of the protein gene itself and location of a defective gene associated with an inherited form of the disease that represents 15 percent of cases.

Dr. Jean-Maurice Delabar and colleagues at the Laboratorie de Biochimie Genetique in Paris conducted the latest research in collaboration with Drs. Dmitry Goldgaber, Paul Brown and D. Carleton Gajdusek of the National Institutes of Health in the United States.

The scientists found three copies of the gene instead of the normal two copies in three patients with the form of Alzheimer’s not believed to be passed down through family lines, said a report to be published Friday in the journal Science.

This same abnormal number of genes was seen in five patients with the most common form of Down’s, a finding that could be anticipated because scientists have long known that these Down’s patients have an extra copy of the chromosome where the gene is found.

But the researchers also said they discovered this same duplication in two Down’s patients with the normal number of chromosomes, a rarer condition. This could explain why those patients also develop Alzheimer’s-like brain changes as they get older even without the extra chromosome, they said.

Genes are small pieces of DNA, or deoxyribonucleic acid, the basic substance of heredity. Strands of DNA containing genes make up the 23 pairs of rod-shaped chromosomes found within every cell that pass on characteristics to subsequent generations.

Down’s syndrome, a disabling condition that is the leading cause of mental retardation, develops when a person has the normal complement of 23 chromosome pairs plus an extra copy of chromosome 21.

No one knowns what causes Alzheimer’s disease, a degenerative condition that results in a buildup of tangled fibers within nerve cells of the brain and scaly plaques in between. The disease normally hits people when they are in their 70s or 80s and robs them of memory, judgment and physical mobility.

Protein strands called amyloids are a major part of Alzheimer’s plaques and possibly are involved in the tangles, experts say. Similar plaques appear in the brains of adult Down’s patients and, to a limited degree, in most people when they get old.

Several research groups, including Goldgaber’s at the National Institute of Neurological and Communicative Disorders and Stroke, recently reported finding a gene on chromosome 21 that is responsible for the precursor proteins that end up as amyloids.

Researchers from Harvard Medical School reported finding a gene on the same segment of chromosome 21 that they traced through families with an inherited form of Alzheimer’s. Some scientists suspect that this might be the same amyloid gene.

In the latest work, researchers used Goldgaber’s genetic tracers for the gene to examine white blood cells from the Alzheimer’s and Down’s patients. These markers located the extra gene copies on chromosome 21.

″Our results support the hypothesis that Alzheimer’s disease involves the duplication of a subsection of the critical segment of chromosome 21 that is duplicated in Down’s syndrome, and this substantiates the existence of a genetic defect in Alzheimer’s disease,″ the researchers reported.

No one yet knows how the Alzheimer’s patients got the extra gene.

However, the researchers speculate that the duplication might have taken place during the process that produces eggs and sperm in parents rather than in early embryonic development after conception.

Since the gene duplication occurs on the same region of chromosome 21 in both diseases, the scientists theorize that this genetic segment might be a ″hot spot,″ an unstable area that is particularly susceptible to aberrations.

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