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Gene mutation finding suggests immune system role in Alzheimer's

Published: Wednesday, Nov. 14 2012 3:03 p.m. MST

Bill Miller spends time with his wife Beverly, who has Alzheimer's, and their grandson Benjamin Miller in their yard in Salt Lake City, Thursday, Oct. 18, 2012. An international collaboration that includes BYU has discovered a rare genetic mutation that greatly increases risk of Alzheimer's disease.

Ravell Call, Deseret News

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An international collaboration that includes BYU has discovered a rare genetic mutation that greatly increases risk of Alzheimer's disease.

Besides adding to a growing body of information about the devastating neurodegenerative disease, the finding is important, researchers said, because the study showed they can use new ways to find genetic mutations that confer risk not only for Alzheimer's, but for other complex diseases.

A rare mutation of TREM2, a gene known to play a role with the immune system, greatly increases the risk of Alzheimer's, the researchers found. Turning off the gene entirely raised the risk of Alzheimer's twofold to sixfold, depending on the data set the researchers used. The mutation occurs, however, only in a small portion of the population, so it's likely only involved with 2 percent of Alzheimer's cases, said John "Keoni" Kauwe, a Brigham Young University geneticist who is a co-author on the study.

The research was published online Wednesday in the New England Journal of Medicine.

"These findings are particularly exciting because they give us a clear signal about what could be going wrong in Alzheimer's disease," said the study's lead author, Dr. Rita Guerreiro of University College London. "While the genetic mutation we found is extremely rare, its effect on the immune system is a strong indicator that this system may be a key player inthe disease. The more we can understand about the causes of Alzheimer's, the better our chances of developing teatments that could stop the disease developing."

Alzheimer's causes are unknown and treatments have been unsuccessful because diagnosis typically occurs after the disease has been crippling the brain for years. The researchers hope to find ways to predict Alzheimer's when the outcome can be impacted, a decade or more before onset.

Ongoing collaboration

According to Kauwe, the London researchers became curious about TREM2 variants because they were finding them more often in cases of the disease than in control cases in their research. They consulted with BYU's Kauwe and researchers from Washington University School of Medicine and the National Institutes of Health initially because the four research centers have done a fair amount of whole-genome sequencing and had already formed an informal collaboration to chase answers to what causes Alzheimer's.

"We meet regularly to discuss how to collaborate with each other to solve the genetics of Alzheimer's disease," said Kauwe. "The hope is this will provide a better therapeutic target than the genes we've already discovered."

The study points to two important things, he said. "The most immediate one is we know something new about what is causing Alzheimer's. We know that this gene and the pathways that it's part of influence the disease process and that's very important. On a broader scale, it's a demonstration that we can use whole-genome data sets to identify rare changes in the human population that confer large differences in risk for complex disease."

As a result of the approach and the collaboration, they have identified "many other very interesting candidates in the pipeline and I anticipate success with additional genes in the near future," he said. Each finding, he noted, brings closer the possibility of novel therapeutic targets that will be more amenable to treatment than the ones they already know.

"These techniques have the potential to identify rare mutations in families or patients in whom linkage analysis cannot be performed and to identify rare variants with moderate-to-strong effects in complex diseases," the study authors wrote.

Kauwe noted that in most Alzheimer's cases, "there's certainly a complex mix of genetic factors as well as environmental ones. When we study genetics, we're really trying to untangle this complex of interactions between different genes and the environment of the individual."

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