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New Studies Link Rare Variant to Alzheimer's Disease Risk

NEW YORK (GenomeWeb News) – A pair of studies that appeared in The New England Journal of Medicine this week identified a rare variant of the TREM2 gene as a potent risk factor for late-onset Alzheimer's disease.

A number of risk variants for Alzheimer's disease have previously been reported, though many of them have been linked to familial early-onset Alzheimer's disease, while others that have been associated with the late-onset form of the disease have generally been shown to confer low risk, with the notable exception of the ε4 allele of apolipoprotein E.

This new variant is thought to increase disease risk by a similar factor as the ε4 allele of apolipoprotein E, which has a reported odds ratio of approximately three.

Using a combination of sequencing and imputation approaches, the two teams of researchers found that the R47H variant of the TREM2 gene, which codes for an innate immune receptor found in the cell membranes of some myeloid cells, is associated with risk of late-onset Alzheimer's disease. This follows previous findings implicating homozygous loss-of-function mutations in TREM2 in a separate form of dementia.

"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," Kari Stefánsson, CEO of Decode Genetics, said in a statement regarding his team's paper.

The Decode Genetics-led team drew on previous work in more than 2,000 Icelanders identifying sequence variants that are likely to affect protein function. The group then imputed those variants into the genomes of 3,550 Alzheimer's disease patients and controls, who were people aged 85 and older who had not developed the disease. From this, the researchers uncovered a link between a missense mutation, R47H, in the TREM2 gene and Alzheimer's disease risk. The mutation leads to a substitution of histidine for arginine at position 47 in the receptor.

The researchers replicated the finding in other cohorts of European ancestry from the United States, Germany, The Netherlands, and Norway.

Similarly, the Alzheimer's Genetic Analysis Group reported in a separate NEJM paper that it, too, linked a TREM2 gene variant to Alzheimer's disease risk. That team combined genome, exome, and Sanger sequencing to analyze the genetic variability of TREM2 in more than 1,000 Alzheimer's disease patients and more than 1,000 controls.

That group found a number of variants in exon 2 of TREM2 in Alzheimer's disease patients, with R47H showing the strongest association with the disease.

In a related editorial in NEJM, Harald Neumann from the University of Bonn in Germany and Mark Daly from Massachusetts General Hospital speculate that the Alzheimer's Genetic Analysis Group found a greater number of variants in TREM2 linked to Alzheimer's disease as it drew upon a more diverse population than the Icelandic study.

The Alzheimer's Genetic Analysis Group confirmed its findings in a meta-analysis and by directly genotyping a second cohort of patients and controls.

Additionally, the group noted that TREM2 expression levels differ between control mice and a mouse model of Alzheimer's disease.

Both research groups say that the R47H variant of TREM2 could lead to partial loss of the function of the TREM2 protein, which plays a role in regulating immune response to disease and injury in the brain. TREM2 has an anti-inflammatory role and it is thought to help clear cell debris and amyloid protein, which makes up the amyloid plaques that are a hallmark of Alzheimer's disease. Its loss, then, could contribute to the buildup of those plaques.

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

The variant, though, is rare. The Decode team reported that the allelic frequency of the R47H variant of TREM2 in the Icelandic population is 0.63 percent, as compared to the more common ε4 allele of apolipoprotein E, which has a population frequency of 17.3 percent.

Both alleles, it added, confer a similar risk of Alzheimer's disease, with a reported odds ratio of between three and four.

The Alzheimer's Genetic Analysis Group echoed those findings. In its study, it found the R47H variant of TREM2 to be present in 1.9 percent of Alzheimer's patients and 0.37 percent of controls.

"The TREM2 variant may be rare, but it is potent," said Minerva Carrasquillo, a scientist from the Mayo Clinic Florida who was part of the Alzheimer's Genetic Analysis Group, in a statement. "This strong effect rivals that of the well-established genetic variant known as APOE 4, and it was observed both in our study and in the independent study led by Decode that was published with ours. R47H isn't fully penetrant — meaning that not all people who have the variant will develop Alzheimer's and in those who do, other genes and environmental factors will also play a role — but like APOE 4 it does substantially increase risk."

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