deCODE genetics and Illumina, together with scientists from the National Hospital of Iceland and collaborators from Holland, Germany and the US, have reported in the New England Journal of Medicine the identification of the second gene variant found to confer high risk of acquiring the more common, late-onset form of Alzheimer's disease (AD). The newly-discovered variant, TREM2, was also found to predict poorer cognitive function in older individuals who do not have AD. The discovery of variant TREM2 is important because it confers high risk for AD and because the gene's normal biological function has been shown to reduce immune response that may contribute to the disease.
While a number of common, low-risk variants have been reported to associate with late-onset AD, the apolipoprotein E-4 (APOE-4) gene allele, 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-4 gene 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 AD. TREM2 has also been shown to exercise a regulatory control of inflammation, which has been associated with AD and cognitive decline.
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 analysed against the genomes of 3,550 persons with AD 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 AD maintained in the US, Germany, the Netherlands and Norway.