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

By Thorlákur Jónsson, Hreinn Stefansson, S. Steinberg, I. Jónsdóttir, Pálmi V. Jónsson, J. Snaedal, Sigurbjorn Bjornsson, J. Huttenlocher, A. Levey, J. Lah and 14 more. New England Journal of Medicine, 2012

2,442 citations recorded by the source corpus.

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.)

Subfields: Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/1ec9d827981b7a478e7075d881005321d3500394

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In Immunology

1. D. Holtzman
2. O. Butovsky
3. M. Colonna
4. Chao Gao
5. Shengdi Chen
6. Yuyan Tan
7. Jingwen Jiang
8. Morgan Sheng

In Neurology

1. D. Holtzman
2. D. Selkoe
3. Chao Gao
4. Shengdi Chen
5. Yuyan Tan
6. Jingwen Jiang
7. R. Ransohoff
8. O. Butovsky

Citations in the corpus

• Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner (2019, background): “Given its recently appreciated centrality in Alzheimer’s disease (Guerreiro et al., 2013; Jonsson et al., 2013; Keren-Shaul et al., 2017; Ulland et al., 2017; Wang et al., 2015), numerous efforts are underway to stimulate TREM2 signaling pharmacologically.”
• Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023, background): “145 These results suggest that microglia respond to the pathology of AD.”
• Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein (2015, positive): “Heterozygous missense mutations in the gene encoding triggering receptor expressed on myeloid 2 cells (TREM2) increase the risk of AD by about threefold (121, 122).”
• TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models (2015, background): “Notably, variants of the immune cell– specific triggering receptor expressed on myeloid cells 2 (TREM2) confer dramatically elevated risk for developing AD (R. Guerreiro et al., 2013; Jonsson et al., 2013).”