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New Alzheimer's Gene Discovery Sparks Hope for Treatments
  By Michelle Fay Cortez
Sept. 7 (Bloomberg) -- The first new genes tied to Alzheimer's disease in a decade have been identified by European scientists, adding insight into the biology of the most common cause of dementia and potentially leading to treatments.
The studies, published yesterday in the journal Nature Genetics, may one day help speed creation of therapies for a malady that progressively destroys brain cells and affects 30 million people worldwide, the investigators said during a Sept. 4 news conference. Doctors already know that as much as 80 percent of a person's chance of having Alzheimer's is inherited.
When working normally, the DNA create proteins that may either calm inflammation or help escort out excess amyloid, a chemical that forms plaque in the brains of disease victims, the researchers said. The new findings, by scientists in Wales and France, suggest the CLU and Picalm genes account for 9 percent of cases each, and the CR1 gene is responsible for 4 percent.
"If we were able to remove the detrimental effects of these genes through treatments, we could reduce the proportion of people developing Alzheimer's by 20 percent," said Julie Williams, the study's lead author and a professor of neuropsychological genetics at Cardiff University in Wales. The findings "could provide valuable new leads in the race to find treatments," she said.
When taken alone, the three new genes can't predict if a person is going to get the disease, and shouldn't be used for screening patients, said Michael Owen, director of the Center for Neuropsychiatric Genetics and Genomics at Cardiff University in Wales and a senior investigator on Williams's study. Instead, they provide part of a more complex picture that may explain why people get Alzheimer's, he said.
Comparing Differences
Williams' study examined the DNA of 3,941 people with Alzheimer's and 7,848 people without it, comparing more than half a million genetic differences to pinpoint those that occurred more often in patients. The researchers repeated the tests in another 4,363 people, evenly split between those with the condition and those without it.
Williams's report identified CLU and Picalm. A second study published in Nature Genetics, by Philippe Amouyel from Institut Pasteur de Lille in France, pinpointed CLU and CR1.
Owen said about 400 genes have been identified that may play a role in the condition, named for the German doctor Alois Alzheimer who described it in 1906. The greatest inherited risk comes from the APOE gene, discovered in 1993 by a team led by Allen Roses, now director of the Deane Drug Discovery Institute at Duke University Medical Center in Durham, North Carolina.
Testing Combinations
Researchers are trying to determine which gene variations, and which combinations, are most important. Owen's group is planning a study next year that will include 60,000 people, examining 10 to 15 gene patterns, he said.
The findings "are beginning to give us insight into the biology, but I don't think you can expect treatments overnight," Owen said. Instead, the genes will show a mosaic of risk, and "the key issue is what hand of cards you're dealt," he said.
Identifying how groups of genes work together may help in studies of experimental drugs. By testing the genetic makeup of study volunteers, investigators may be able to identify pools of patients who are most likely to develop the disease, according to the Pasteur Institut's Amouyel.
Finding such an "enhanced" population could speed development and improve study results, he said.
Destroys Brain Cells
Alzheimer's destroys brain cells, making it difficult for patients to think, remember and function. The condition is still only definitively diagnosed at autopsy, when amyloid protein plaques in the brain can be seen.
The number of people worldwide with the condition is expected to swell to 120 million by 2050, and there are no effective treatments. Existing medications have only been found to ease symptoms temporarily.
The researchers led by Amouyel initially studied 2,032 French patients with Alzheimer's disease and 5,328 healthy comparisons. They confirmed the results in another 7,500 people from Belgium, Finland, Italy and Spain. The similarity between his results and Williams's adds weight to the significance, Amouyel said.
"We didn't know before we finished the studies that we had the same genes," Amouyel said. "The chance of that happening by accident is very low."
Numerous Questions Unanswered
There are still numerous questions to be answered, Williams and Amouyel both said.
The genetic variations are common, it's not always clear what they are doing, or which mutations are crucial to the development of Alzheimer's disease. They also have a number of functions, many beneficial, the researchers said.
"Perhaps the changes we see in these genes remove this protection or may even turn them into killers," Cardiff University's Williams said.
The CLU gene produces clusterin, which may protect the brain against damage from pathogens or kick in to calm an inflammatory response, Williams said. Others seem to escort out excess amyloid, the plaque that builds up in patients' brains.
The findings drew a varied response from within the Alzheimer's community.
Roses, who identified the APOE gene, said the biological implications for new genes were inflated in the reports. The effects of the newly discovered genes are statistically correct, Roses said in an e-mailed response to questions.
He said the researchers didn't properly account for current knowledge of the pathogenesis and biology of Alzheimer's disease, leading them to over-estimate the relevance.
'Leap Forward'
Rebecca Wood, chief executive of the Alzheimer's Research Trust in Cambridge, U.K., called the findings "a leap forward" for dementia research.
"At a time when we are yet to find ways of halting this devastating condition, this development is likely to spark off numerous new ideas, collaborations and more in the race for a cure," she said in a statement.
Williams's Genome-Wide Association Study was funded by the Medical Research Council, the Wellcome Trust, the Welsh Assembly Government, the Alzheimer's Research Trust and others. Amouyel's research was funded by Fondation Nationale de Cooperation Scientifique.
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