Rare Mutation of TREM2 Gene Related to Immune System and Inflammation Increases Risk of AD

Two different international groups of researchers independently and almost simultaneously discovered a rare mutation of an Immune System related gene named TREM2 increases risk of AD either 3-fold (the Icelandic group led by Kari Stefansson at DeCode Genetics) or 5-fold (the UK international group led by Alzheimer Genetic Analysis Group & John Hardy at the UCL Institute of Neurology, London).  Their findings are reported in the New England Journal of Medicine November 14 2012 on line edition.

For the gene TREM2, certain loss-of-function mutations had previously been associated with an autosomal recessive form of early-onset dementia.

The UK group looked at 1092 patients with Alzheimer’s disease and 1107 controls (the discovery set)  to identify the TREM2 mutant genes/alleles, and also did meta-analyses and looked at unrelated databases of patients and controls to replicate and verify their initial findings.  This group also assayed the expression of TREM2 across different regions of the human brain and looked at differential gene expression in AD and control mice to clarify genetic mutations and disease mechanisms.

Iceland group finds Immune System related rare gene TREM2 increases risk of AD 3-fold.  In the study, researchers from DeCode Genetics analyzed 2,261 Icelanders and found those with a variant, or defect, on a gene called TREM2 had almost a three times higher likelihood of Alzheimer’s disease than those without the mutation. The scientists also tested a combined 2,000 people in four other groups from the U.S. and Europe, finding similar results.

The Icelandic researchers determined that carriers of the mutation who were at least 80 years old and without Alzheimer’s disease had poorer cognitive function than their unmutated peers. Authors conclude, ” Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer’s disease. Given the reported anti-inflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer’s disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.)   Check out the full article at New England Journal of Medicine.

According to Andrew Budson, MD of the BU Alzheimer’s Disease Center and Boston Memory Clinic who studied with him, over a decade ago Dr. Stefansson began by asking the question, how are 75 year olds newly admitted to nursing homes with dementia, different from 85 year olds with same condition.  Dr. Steffansson’s genetic research has led to uncovering several chronic disease related genes.

These two studies further underscore the importance of foods and other healthy lifestyles that decrease inflammation in body and brain. See BrainWellness.com for more details on how the Memory Preservation Nutrition® is designed to reduce inflammation. Regular physical exercise also reduces inflammation; smoking increases it.

Hardy UK group:

Original Article abstract

TREM2 Variants in Alzheimer’s Disease

Rita Guerreiro, Ph.D., Aleksandra Wojtas, M.S., Jose Bras, Ph.D., Minerva Carrasquillo, Ph.D., Ekaterina Rogaeva, Ph.D., Elisa Majounie, Ph.D., Carlos Cruchaga, Ph.D., Celeste Sassi, M.D., John S.K. Kauwe, Ph.D., Steven Younkin, M.D., Ph.D., Lilinaz Hazrati, M.D., Ph.D., John Collinge, M.D., Jennifer Pocock, Ph.D., Tammaryn Lashley, Ph.D., Julie Williams, Ph.D., Jean-Charles Lambert, Ph.D., Philippe Amouyel, M.D., Ph.D., Alison Goate, Ph.D., Rosa Rademakers, Ph.D., Kevin Morgan, Ph.D., John Powell, Ph.D., Peter St. George-Hyslop, M.D., Andrew Singleton, Ph.D., and John Hardy, Ph.D. for the Alzheimer Genetic Analysis Group

November 14, 2012DOI: 10.1056/NEJMoa1211851

Background

Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.

Methods

We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer’s disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer’s disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer’s disease and in control mice.

Results

We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer’s disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer’s disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer’s disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer’s disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer’s disease.

Conclusions

Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer’s disease. (Funded by Alzheimer’s Research UK and others.)

 

ICELAND GROUP

Abstract

Variant of TREM2 Associated with the Risk of Alzheimer’s Disease

Thorlakur Jonsson, Ph.D., Hreinn Stefansson, Ph.D., Stacy Steinberg Ph.D., Ingileif Jonsdottir, Ph.D., Palmi V. Jonsson, M.D., Jon Snaedal, M.D., Sigurbjorn Bjornsson, M.D., Johanna Huttenlocher, B.S., Allan I. Levey, M.D., Ph.D., James J. Lah, M.D., Ph.D., Dan Rujescu, M.D., Harald Hampel, M.D., Ina Giegling, Ph.D., Ole A. Andreassen, M.D., Ph.D., Knut Engedal, M.D., Ph.D., Ingun Ulstein, M.D., Ph.D., Srdjan Djurovic, Ph.D., Carla Ibrahim-Verbaas, M.D., Albert Hofman, M.D., Ph.D., M. Arfan Ikram, M.D., Ph.D., Cornelia M van Duijn, Ph.D., Unnur Thorsteinsdottir, Ph.D., Augustine Kong, Ph.D., and Kari Stefansson, M.D., Ph.D.

November 14, 2012DOI: 10.1056/NEJMoa1211103

Background

Sequence variants, including the ε4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer’s disease. Few rare variants affecting the risk of late-onset Alzheimer’s disease have been found.

Methods

We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer’s disease and control participants and then tested for an association with Alzheimer’s disease. We performed replication tests using case–control series from the United States, Norway, the Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons.

Results

A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer’s disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42×10−10). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10−12 in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer’s disease had poorer cognitive function than noncarriers (P=0.003).

Conclusions

Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer’s disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer’s disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.)

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