TREM2 Variants in Alzheimer's Disease

By R. Guerreiro, Aleksandra M. Wojtas, J. Bras, M. Carrasquillo, E. Rogaeva, E. Majounie, Carlos Cruchaga, C. Sassi, J. Kauwe, S. Younkin and 14 more. New England Journal of Medicine, 2012

2,718 citations recorded by the source corpus.

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.)

Subfields: Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/0f6f50c0fb645ee11109eb8d27e6ea22e03e36e1

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

In Neurology

Citations in the corpus

Neuroinflammation in Alzheimer's disease: Current evidence and future directions (2016, background): “and inflammation on the other hand [36], reinforcing the hypothesis of a causative link between inflammatory cells and degeneration.”
Inflammation as a central mechanism in Alzheimer's disease (2018, background): “[133] Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al.”
APP mouse models for Alzheimer's disease preclinical studies (2017, neutral): “There are other potential points for prevention at this stage, such as mechanism(s) by which A b amyloidosis affects tauopathy or by which TREM2 (Guerreiro et al , 2013; Jonsson & Stefansson, 2013) influences pathogenesis and these may also be studied in mouse models for A b pathology.”
Hallmarks of neurodegenerative diseases. (2023, neutral): “234 TREM2 genetic variants are also associated with risk for AD in the heterozygous state, 235,236 and TREM2, in concert with apoli-poprotein E (ApoE), plays a crucial role in the transition of homeostatic microglia to microglia associated with disease phenotypes.”
Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein (2015, neutral): “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).”
Alzheimer's disease risk genes and mechanisms of disease pathogenesis (2014, neutral): “Additionally, rare coding variants were identified in TREM2 in sequencing studies of LOAD cohorts (9,10).”
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023, background): “145 These results suggest that microglia respond to the pathology of AD.”
The amyloid hypothesis of Alzheimer's disease at 25 years (2016, background): “The upregulation of TREM2 in a subset of microglia in amyloid plaques of hAPP tg mice (e.g., Guerreiro et al, 2013) suggests that the known function of TREM2 in phagocytosis is compromised during plaque development.”