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Gene Variant May Hike Women's Risk of Alzheimer's

Men can carry the variation as well, study finds

MONDAY, Jan. 12 (HealthDay News) -- Scientists have discovered a gene variant on the X chromosome that appears to increase the risk of developing Alzheimer's disease.

The risk was most pronounced in women with the variant on both X chromosomes, although both women and men with just one variant of the gene were also at greater risk.

"What you have in a nutshell is the first study showing a gene on the X chromosome and the first sex-specific effect [for Alzheimer's]," said Dr. Steven Younkin, senior author of the paper published online Jan. 11 in the journal Nature Genetics. "It does not mean women are at increased risk for Alzheimer's."

Although the presence of the mutation offers strong evidence of a heightened risk, further research needs to be done to determine how big of a risk, added Younkin, who is the George M. Eisenberg professor of neuroscience at the Mayo Clinic College of Medicine in Jacksonville, Fla.

Dr. Anton Porsteinsson, director of the Alzheimer's Disease Care, Research and Education Program and the Memory Disorders Clinic at the University of Rochester School of Medicine, called the finding intriguing.

"To me, the fact that it's X-linked is intriguing because of the fact that there are more women than men with Alzheimer's disease," he said.

According to background information in the paper, late-onset Alzheimer's disease is the most common cause of dementia in older people, affecting about 10 percent of those aged 65 or over.

A mutation in the APOE 4 gene is the only genetic risk factor that has been "solidly" linked to the risk of late-onset Alzheimer's, Porsteinsson said. Other genes have been linked to early onset disease.

"The effort to find additional genetic variants has been difficult," Younkin said.

For the study, Younkin and his colleagues scanned hundreds of thousands of genes in 844 people with Alzheimer's disease and 1,255 healthy people who served as "controls."

There was nothing genetic in the first pass that the researchers could say unequivocally was associated with Alzheimer's disease.

But a second pass, this one on even more patients and controls, uncovered a strong association between a mutation on the PCDH11X gene and Alzheimer's disease.

"It was significant enough to convince us we had something real," Younkin said.

The findings were given added weight because the researchers examined autopsies on participants who had died to confirm the diagnosis of Alzheimer's. Clinical diagnoses are about 90 percent accurate anyway, Porsteinsson said.

Women with two copies of the gene had a 75 percent increased risk for Alzheimer's. Women with only one copy of the gene had a 26 percent increased risk, while men with one copy had an 18 percent increased risk.

The gene is part of a family of genes linked with the nervous system and are involved in cell adhesion.

"We're basically looking at a finding that seems to encode a gene that has something to do with central nervous system development," Porsteinsson said. "And Alzheimer's is ultimately a central nervous system disease."

It's unclear how the gene may actually work to increase the risk of Alzheimer's. Once that is known, however, the search for new treatments could be accelerated, the researchers said.

"It's trite but true -- the reason we all search for genes is that every one opens a door to identify people at risk, and every one opens a door to identify potential therapies if we can understand how it works," Younkin said.

But first, these findings need to be replicated. "This just means a lot of work ahead," Porsteinsson said.

More information

To learn more, visit the Alzheimer's Association.

SOURCES: Steven Younkin, M.D., Ph.D., George M. Eisenberg professor of neuroscience, Mayo Clinic College of Medicine, Jacksonville, Fla.; Anton Porsteinsson, M.D., director, Alzheimer's Disease Care, Research and Education Program, and director, Memory Disorders Clinic, and associate professor of psychiatry, University of Rochester School of Medicine, Rochester, N.Y.; Jan. 11, 2009, Nature Genetics, online

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