Findings Published in New England Journal of Medicine Provide New Focus for Drug Discovery Study Demonstrates Power of “Big Data” Research

REYKJAVIK, Iceland – deCODE Genetics and Illumina, global leaders in analyzing and understanding the human genome, together with scientists from the National Hospital of Iceland and collaborators from Holland, Germany and the United States, reported today in the New England Journal of Medicine the identification of just the second gene variant found to confer high risk of acquiring the more common, late-onset form of Alzheimer’s disease. The newly discovered variant was also found to predict poorer cognitive function in older individuals who do not have Alzheimer’s disease.

“Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer’s disease”

“The discovery of variant TREM2 is important because it confers high risk for Alzheimer’s and because the gene’s normal biological function has been shown to reduce immune response that may contribute to the disease,” said study lead author Kari Stefánsson, M.D., Dr. Med., CEO of deCODE Genetics. “These combined factors make TREM2 an attractive target for drug development.”

While a number of common, low-risk variants have been reported to associate with late-onset Alzheimer’s, the ε4 allele of Apolipoprotein E, originally discovered as a risk factor for the disease in 1993, has been the most important sequence variant because of its prevalence in the population and the size of its effect on risk.

TREM2, while rarer in the general population than the ApoE ε4 allele, confers comparable risk of the disease and plays a significant role in the central nervous system. In preclinical studies, TREM2 has been found to regulate the clearing of cell debris and amyloid protein, a component of the amyloid plaques associated with Alzheimer’s disease. TREM2 has also been shown to excersize a regulatory control of inflammation, which has been associated with Alzheimer’s and cognitive decline.

“Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer’s disease,” said Dr. Stefánsson. “Reduced TREM2 activity may lead to brain damage through increased inflammatory response.”

“Big Data” Research

Focusing specifically on variants likely to impact protein function, and thereby honing in on potential targets for drug development, deCODE’s scientists sought additional high-risk variants for Alzheimer’s disease.

Through the company’s genome sequencing and genotyping, deCODE researchers identified approximately 41 million markers, including 191,777 functional variants, from 2,261 Icelandic samples. These variants were then analyzed against the genomes of 3,550 persons with Alzheimer‘s disease and a control population over the age of 85 without a diagnosis of the disease. The association analysis used to identify the variant TREM2 in the Icelandic population was then replicated against other control populations with Alzheimer‘s disease maintained in the United States, Germany, the Netherlands and Norway.

“Using this approach, we have recently reported variants that greatly influence the risk of developing other diseases, including ovarian cancer, gliomas, gout and sick sinus syndrome,” said Dr. Stefánsson. “So-called big data research has evolved to a new level of sophistication due to new research tools, access to expanded and high quality genomic data sets, and certainly the profound analytic skill level of investigators now combining sequence data and biological knowledge to find drug targets.”