Might is right

Four new Alzheimer’s disease genes discovered by UPenn-led consortium double known contributing genes

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PHILADELPHIA, Pa.—Four new genes linked to Alzheimer's disease have been identified, thanks to a consortium led by the University of Pennsylvania School of Medicine, the University of Miami and the Boston University School of Medicine. Individually, each gene increases a person's risk of having Alzheimer's, and together, the genes offer new opportunities into learning more about the cause of this disease and possible future treatments.

The study resulted from a collaborative effort of investigators from 44 research institutions and universities in the United States, led by Dr. Gerard D. Schellenberg at Penn, with primary analysis sites at Miami, led by Dr. Margaret Pericak-Vance, and Boston, led by Dr. Lindsay Farrer. The consortium, titled the Alzheimer's Disease Genetics Consortium, has been in the making for nearly three years, Schellenberg says.

The study reports the genetic analysis of more than 11,000 people with Alzheimer's disease, as well as nearly the same number of elderly people with no symptoms of dementia. Confirming data from additional people was contributed by three other consortia, which brought the total number of people analyzed to more than 54,000. In addition to the four genes discovered, the consortium also aided in identifying a fifth gene reported by groups of investigators from the United States, the United Kingdom, France and other European countries, and the findings can be found in the current issue of Nature Genetics.

"This is the culmination of years of work on Alzheimer's disease by a large number of scientists, yet it is just the beginning in defining how genes influence memory and intellectual function as we age," Schellenberg states.

The new genes are MS4A, CD2AP, CD33 and EPHA1, and the study's scientists also contributed to the identification and confirmation of two other genes, BIN1 and ABCA7, doubling the number of genes known to contribute to Alzheimer's.

Schellenberg says that the researchers weren't focusing on anything particular when they discovered the new genes, explaining that "it's not really starting with a hypothesis, it's a process where you generate new ideas." He emphasizes that they went into the study without "a preconceived idea about which gene it's going to be," and looked across the entire genome.

"The real payoff of this is our genetic data says these genes have to be involved in your risk for Alzheimer's," Schellenberg says. "And now starts the hard part, saying 'okay, how does this fit into Alzheimer's disease and what does the gene do normally, and what does it contribute when things start to go wrong in the brain.'"

Until this discovery, only four genes associated with late-onset Alzheimer's have been confirmed, and the gene for apolipoprotein E-e4, APOE-e4, has the greatest effect on risk. Schellenberg notes there are also three early-onset genes that are autosomal dominant, ensuring that someone with those genes will develop the disease, though he adds that they are "an extremely rare cause of Alzheimer's disease." The first risk gene, he says, was discovered in 1992.

From here on out, the researchers will focus on identifying new Alzheimer's disease risk genes and on working further with the recently discovered genes to learn more about them and determine their contributions to Alzheimer's. As more risk genes are identified, researchers will be able to detect the initial stages of the disease, which will help in identifying the cause and tracking the progression of Alzheimer's.

"I think the first thing that will come along is a treatment," Schellenberg says of where the genes' discovery will lead. "Prevention is what we all really want, and one of the goals of all research is trying to figure out what's the very first thing that happens that starts the Alzheimer's process."

Researchers focusing on the genetics of Alzheimer's are forming a similar, but larger, study. The International Genomics of Alzheimer's Project, funded by the Alzheimer's Association in the United States and the Fondation Plan Alzheimer in France, had its first meeting in November 2010 in Paris.

"We are all tremendously excited by our progress so far, but much remains to be done, both in understanding the genetics and in defining how these genes influence the disease process," says Schellenberg.

The prevalence of Alzheimer's disease ranges between 3 percent and 5 percent in people ages 65-69 years old, and jumps to about 30 percent to 40 percent in people ages 85-89 years old. Three million to five million people in the United States have Alzheimer's disease, with 35 million people stricken worldwide. As the U.S. population ages, it's expected that those with Alzheimer's disease will number between 8 million and 16 million by the year 2050, with 1 in every 45 Americans affected.

The research that was published in Nature Genetics was supported by the National Institute on Aging, a part of the National Institutes of Health, which includes 29 Alzheimer's Disease Centers, the National Alzheimer's Coordinating Center, the NIA Genetics of Alzheimer's Disease Data Storage Site, the NIA Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease. These centers collect and store DNA samples, genetic analysis data and datasets containing biomedical and demographic information about participants, and make them available to qualified researchers.

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