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Gene Variations On The X Chromosome Are Associated With Increased Susceptibility To Alzheimer's Disease

January 12, 2009

Adapted from the Mayo Clinic

Researchers at Mayo Clinic have discovered the first gender-linked susceptibility gene for late-onset Alzheimer's disease.

In the January 11, 2009 online edition of Nature Genetics, scientists report the results of their two-stage genome-wide association study of patients with Alzheimer's disease. The research showed that women who inherited two copies of a variant in the PCDH11X gene, found on the X chromosome, are at considerably greater risk of developing Alzheimer's disease. Women with a variant on one of their two X chromosomes also had some increase in risk, as did men with the variant on their single X chromosome, but these effects were weaker than inheriting two variants.

Investigators caution that more study is required before assigning the definitive degree of risk the gene seems to carry, but they say it appears to be one of the stronger risk factors found to date.

"This is a very common genetic variant, and many women who had two copies of it did not have disease. But, overall, the odds were substantially greater that female patients with the disease did have two copies," says the study's senior investigator, Steven Younkin, M.D., Ph.D., a consultant-researcher at Mayo Clinic's campus in Florida and George M. Eisenberg, Professor of Neuroscience in the College of Medicine. "The results obtained do not imply that women are generally at increased risk for developing the disease than men."

The Mayo group first detected a variant in the gene PCDH11X, which associates with susceptibility to Alzheimer's disease, by scanning the entire genome of 844 patients affected with Alzheimer's disease and 1,255 unaffected control subjects. The association was confirmed by studying an additional 1,547 patients and 1,209 controls.

"When we compared Alzheimer's disease patients with unaffected controls, the largest and most significant difference was in women with two copies of the PCDH11X variant, who were found more frequently in the Alzheimer's disease group," Dr. Younkin says.

"It is always exciting to identify a new Alzheimer's disease gene," says Minerva Carrasquillo, Ph.D., instructor of neuroscience and first author of the study. "The search for genes that influence the risk of common complex diseases such as Alzheimer's disease has proven extremely difficult, as most of the genes involved in the etiology of such diseases tend individually to have only modest effects on risk.

"When we set out to scan the genome for Alzheimer's disease susceptibility genes, we were not at all certain that we would find any gene other than the well-established APOE gene. Fortunately, the unbiased genome-wide scan that we undertook enabled us to identify PCDH11X, a previously unsuspected gene on the X chromosome that is the first to show gender-specific effects."

Dr. Younkin says, "Even though this is a large study showing highly significant association, it is important to analyze many additional Alzheimer's disease cases and controls before drawing any final conclusions about the strength of the association and the degree of risk it confers on developing Alzheimer's disease."

"The goal now will be to conduct further studies of this gene to determine the precise mechanism by which genetic variation in PCDH11X influences the risk of Alzheimer's disease and if the findings can be translated to improved diagnostics and therapeutics," Dr. Carrasquillo says.

View all news updates for Alzheimer's disease


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Some of the content in this section is adapted from other sources, which are clearly identified within each individual item of information.

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