Variant ofTREM2Associated with the Risk of Alzheimer's Disease

Abstract

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.)

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

“…Findings are strongest for the innate immune response, for instance association with the TREM2 gene, which in brain cells are primarily expressed on microglia 45, 46. Our findings further support the role of immune variation in AD susceptibility.…”

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

“…We also included known early‐onset AD genes and genes implicated in earlier sequencing efforts in LOAD 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16. Candidate genes evaluated included: APP, PSEN1, PSEN2, GRN, MAPT, TREM2, PLD3, APOE, ABCA7, SORL1, CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, CD33, HLA‐DRB5, HLA‐DRB1, PTK2B, SLC24A4, RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, TREML2, and AKAP9 .…”

“…Common variants identified through GWAS may not have functional consequences, simply reflecting linkage disequilibrium with the unobserved causal variants. It is also possible that these causal variants are rare and have large effects, such as TREM2, 7, 8, 9, 10, 11, 12, 13 and are not covered by commercially available GWAS platforms. In fact, putatively damaging variants have already been identified (for example TREM2 , SORL1, and ABCA7 ) in some of these LOAD susceptibility loci, advancing our understanding of disease risk 14, 15, 16…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Changes related to microglia, the resident macrophages of the CNS, have long been considered to be secondary events to neurodegeneration but are now emerging as central to AD risk (Guerreiro et al, 2013; Jonsson et al, 2013; Lambert et al, 2013; Salter & Stevens, 2017; Zhang et al, 2013). GWAS repeatedly identified SNPs on TREM2, CD33, CD1, etc., which are all expressed on microglia and myeloid cells, as AD risk factors.…”