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.
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."
Lots of subjects
They looked at the complete genomes of 281 patients with Alzheimer's and 504 who didn't have it, including 175 elderly people. When they found a "disproportionate number of variants" in the TREM2 of people with the disease, they expanded the research and used other sequencing and study techniques to look at more than 1,000 individuals with Alzheimer's, as well as that many without. All were of European and North American descent.
They also reached out to other centers and experts to look at TREM2 in various ways, from mice with human mutations known to cause the disease, to other ways of replicating the association. It was clear that TREM2 is one of the genes that changes the most in its expression between normal mice and mice with Alzheimer's, Kauwe said. They also looked at brain sections of people who had the mutation to see that they "did have clean, clear-cut, diagnosable Alzheimer's disease, which they did."
They confirmed what they found in a still-broader base, analyzing data from 6,675 people with Alzheimer's and 16,242 without. One variant of TREM2, called R47H, had a particularly strong association with the disease.
A release from London said the TREM2 gene "controls a protein that is involved in regulating the immune response to injury or disease, acting as an on/off switch for immune cells in the brain called microglia. The R47H variant of the gene results in a partial loss of this function, with less ability to keep cell activity in check, "potentially causing them to become hyperactive."
Other centers involved in the research were the Mayo Clinic, University of Toronto, U.S. National Institute of Aging, King's College London, University of Nottingham, Tanz Centre for Research in Neurodegenerative Diseases, Istanbul University, Utah State University, University of Coimbra, Medical University of Lodz, University of Perugia, University of Kuopio, Aristotle Univesity of Thessaloniki, Hospital La Grave-Casselardit, University of Manchester, Universite Lille Nord de France, Cardiff University and University of Cambridge.
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