Alternative titles; symbols
DO: 0110049;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.1 | {Alzhieimer disease 17, susceptibility to} | 615080 | Autosomal recessive | 3 | TREM2 | 605086 |
A number sign (#) is used with this entry because of evidence that susceptibility to the development of late-onset Alzheimer disease-17 (AD17) is conferred by homozygous or compound heterozygous mutation in the TREM2 gene (605086) on chromosome 6p21. Heterozygosity is associated with later age at onset.
For a general phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease, see 104300.
Guerreiro et al. (2013) performed pathologic examination of 5 brains from individuals carrying possibly pathogenic variants in the TREM2 gene (605086). All had fully developed Alzheimer disease and had typical findings with no distinguishing features. Two carriers of the R47H variant (rs75932628; 605086.0008) showed pathologic features of Alzheimer disease in the form of mature and diffuse plaques. Severe cerebral amyloid angiopathy was evident with the presence of parenchymal capillary involvement and circumferential deposition of beta-amyloid (104760). Neuritic plaques, neurofibrillary tangles, and abundant neuropil threads were also present. A carrier of the D87N variant (rs142232675) had mature plaques along with more diffuse plaques and a moderate degree of cerebral amyloid angiopathy, all typical features of Alzheimer disease.
Jonsson et al. (2013) studied the genome sequences of 2,261 Icelanders and identified sequence variants that were likely to affect protein function, and then imputed these variants to the genomes of patients with Alzheimer disease and control participants and tested for association. Jonsson et al. (2013) performed replication tests using case control series from the United States, Norway, the Netherlands, and Germany, and subsequently tested for a genetic association with cognitive function in a population of unaffected elderly persons. A rare missense mutation, rs75932628T (R47H; 605086.0008), in the gene encoding TREM2 on chromosome 6p21.2 was responsible for a significant risk of Alzheimer disease in Iceland (odds ratio, 2.92; 95% confidence interval, 2.09 to 4.09; p = 3.42 x 10(-10)). The mutation had a frequency of 0.46% in controls 85 years of age or older. This association was observed in additional sample sets (odds ratio = 2.90; 95% confidence interval, 2.16-3.91; p = 2.1 x 10(-12) combined discovery and replication samples). Jonsson et al. (2013) found that carriers of rs75932628T between the ages of 80 and 100 years without Alzheimer disease had poorer cognitive function than noncarriers (p = 0.003). Jonsson et al. (2013) concluded that their findings strongly implicated variant TREM2 in the pathogenesis of Alzheimer disease and, given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer disease through impaired containment of inflammatory processes.
Because homozygous loss-of-function mutations in TREM2 had been associated with an autosomal recessive form of early-onset dementia (see 221770), Guerreiro et al. (2013) used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1,092 patients with Alzheimer disease and 1,107 controls (the discovery set). They then performed a metaanalysis on imputed data for the TREM2 R47H variant from 3 genomewide association studies of Alzheimer disease and tested for the association of the variant with the disease. Guerreiro et al. (2013) found significantly more variants in exon 2 of TREM2 in patients with Alzheimer disease than in controls in the discovery set (p = 0.02). There were 22 variant alleles in 1,092 patients with Alzheimer disease and 5 variant alleles in 1,107 controls (p less than 0.001). The most commonly associated variant, R47H, showed a highly significant association with Alzheimer disease (p less than 0.001). Metaanalysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (p = 0.002), as did direct genotyping of an additional series of 1,887 patients with Alzheimer disease and 4,061 controls (p less than 0.001). TREM2 expression differed between control mice in the mouse model of Alzheimer disease. Guerreiro et al. (2013) identified 22 variants in exon 2, 6 of which were not identified among controls. Of these variants, rs142232675T (D87N) was associated with disease (p = 0.02).
Several groups commented on the studies of Guerreiro et al. (2013) and Jonsson et al. (2013). Reitz and Mayeux (2013) examined the TREM2 gene for association with Alzheimer disease in their cohort from the Alzheimer's Disease Genetics Consortium, which included multiple datasets from a total of 5896 black patients (1,968 cases and 3,928 controls). The SNP rs75932628 reported by Guerreiro et al. (2013) and Jonsson et al. (2013) did not pass quality control; however, another SNP in linkage disequilibrium, rs7748513, was significantly associated with Alzheimer disease (p = 0.001). Bertram et al. (2013) genotyped the rs75932628 T allele in 6,421 samples from family-based and case-control data sets. A metaanalysis that combined sample-specific results revealed weak, but nominally significant, support of an association between the T allele at rs75932628 and an increased risk of Alzheimer disease (p less than or equal to 0.05). The effect size found in their study suggested a substantially lower odds ratio of approximately 1.7. Bertram et al. (2013) concluded that the tiny population effect and reduced penetrance of the T allele at rs75932628 in TREM2 limits its usefulness as either a predictor or diagnostic for Alzheimer disease. Rajagopalan et al. (2013) mapped the effects on the brain of the risk allele of rs9394721, a proxy (r(2) = 0.492) of the risk variant of rs75932628 in TREM2, in a cohort of 478 elderly individuals (283 men and 195 women; 100 participants had Alzheimer disease, 221 had mild cognitive impairment, and 157 were healthy controls). The TREM2 mutation carriers annually (over 24 months) lost 1.4 to 3.3% more brain tissue than noncarriers in a pattern that mirrored the profile of Alzheimer disease in the brain. Mutation carriers lost brain tissue twice as fast as healthy elderly people. Benitez and Cruchaga (2013) found an association of the R47H variant (rs75932628T) with Parkinson disease among 1,132 patients with Parkinson disease and 1,387 controls. Bird (2013) noted that in 1983 he and colleagues suggested a possible relationship between Nasu-Hakola disease (221770) and Alzheimer disease, based on the finding of a mutation in TREM2 in a family with Nasu-Hakola disease and an abundance of senile plaques and neurofibrillary tangles in a 48-year-old member of that family. Jonsson and Stefansson (2013) replied to these comments. They were not able to replicate the findings of Benitez and Cruchaga (2013) in an Icelandic population. Guerreiro and Hardy (2013) also replied.
In a study using pooled sequencing of 2,082 AD cases and 1,648 cognitively normal elderly controls of European American descent, Jin et al. (2014) identified 16 nonsynonymous variants in the TREM2 gene, of which 2 were significantly associated with disease risk in single variant analysis: R47H (odds ratio (OR) 2.63, p = 0.000917) and R62H (605086.0009) (OR 2.36, p = 0.000236). Additional variants were likely also to confer risk, as the association was still highly significant even after excluding R47H (OR 2.47, p = 0.000000537).
Li et al. (2021) performed a metaanalysis of 26 datasets comprising 28,007 AD cases and 45,121 controls. A significantly increased risk of AD was observed in R47H carriers versus noncarriers (OR 3.88, 95% CI, 3.17-4.76, p less than 0.001), R62H (OR 1.37, 95% CI, 1.11-1.70, p = 0.004), and H157Y (OR 4.22, 95% CI, 1.93-9.21, p less than 0.001). All of these variants are present primarily in individuals of European descent.
In a metaanalysis of of 24,808 Alzheimer disease patients and 1,165,514 controls examining the role of missense variants in the TREM2, Stefansson et al. (2024) identified R47H as having an incomplete recessive effect (homozygotes for this variant are at a much greater risk of AD than heterozygotes). Individuals who were compound heterozygous for the R47H and R62H alleles had a higher risk of earlier onset of AD than heterozygotes for either, but much less risk than R47H homozygotes. Stefansson et al. (2024) noted that R47H homozygosity does not contribute to amyloid-beta overproduction but instead disrupts amyloid-beta clearance, leading to the accumulation of amyloid plaques.
Association with TREML2
Benitez et al. (2014) reported comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, metaanalyses (16,254 cases of Alzheimer disease and 20,052 controls), and cell-based functional studies to support the role of the TREML2 (609715) coding missense variant S144G (rs3747742) as a potential driver of the metaanalysis Alzheimer disease-associated genomewide association studies signal. Additionally, Benitez et al. (2014) demonstrated that the protective role of TREML2 in Alzheimer disease is independent of the role of the TREM2 gene (605086) as a risk factor for the disease.
Benitez, B. A., Cruchaga, C. TREM2 and neurodegenerative disease. (Letter) New Eng. J. Med. 369: 1567-1568, 2013. [PubMed: 24131187] [Full Text: https://doi.org/10.1056/NEJMc1306509]
Benitez, B. A., Jin, S. C., Guerreiro, R., Graham, R., Lord, J., Harold, D., Sims, R., Lambert, J.-C., Gibbs, J. R., Bras, J., Sassi, C., Harari, O., and 34 others. Missense variant in TREML2 protects against Alzheimer's disease. Neurobiol. Aging 35: 1510.e19-e26, 2014. Note: Electronic Article. [PubMed: 24439484] [Full Text: https://doi.org/10.1016/j.neurobiolaging.2013.12.010]
Bertram, L., Parrado, A. R., Tanzi, R. E. TREM2 and neurodegenerative disease. (Letter) New Eng. J. Med. 369: 1565 only, 2013. [PubMed: 24131185] [Full Text: https://doi.org/10.1056/NEJMc1306509]
Bird, T. D. TREM2 and neurodegenerative disease. (Letter) New Eng. J. Med. 369: 1568 only, 2013. [PubMed: 24131188] [Full Text: https://doi.org/10.1056/NEJMc1306509]
Guerreiro, R., Hardy, J. Reply to TREM2 and neurodegenerative disease. (Letter) New Eng. J. Med. 369: 1569-1570, 2013. [PubMed: 24143816] [Full Text: https://doi.org/10.1056/NEJMc1306509]
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majournie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., Hazrati, L., Collinge, J., and 12 others. TREM2 variants in Alzheimer's disease. New Eng. J. Med. 368: 117-127, 2013. [PubMed: 23150934] [Full Text: https://doi.org/10.1056/NEJMoa1211851]
Jin, S. C., Benitez, B. A., Karch, C. M., Cooper, B., Skorupa, T., Carrell, D., Norton, J. B., Hsu, S., Harari, O., Cai, Y., Bertelsen, S., Goate, A. M., Cruchaga, C. Coding variants in TREM2 increase risk for Alzheimer's disease. Hum. Molec. Genet. 23: 5838-5846, 2014. [PubMed: 24899047] [Full Text: https://doi.org/10.1093/hmg/ddu277]
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., Rujescu, D., Hampel, H., and 12 others. Variant of TREM2 associated with the risk of Alzheimer's disease. New Eng. J. Med. 368: 107-116, 2013. [PubMed: 23150908] [Full Text: https://doi.org/10.1056/NEJMoa1211103]
Jonsson, T., Stefansson, K. Reply to TREM2 and neurodegenerative disease. (Letter) New Eng. J. Med. 369: 1568-1569, 2013. [PubMed: 24131183] [Full Text: https://doi.org/10.1056/NEJMc1306509]
Li, R., Wang, X., He, P. The most prevalent rare coding variants of TREM2 conferring risk of Alzheimer's disease: A systematic review and meta-analysis. Exp. Ther. Med. 21: 347, 2021. [PubMed: 33732320] [Full Text: https://doi.org/10.3892/etm.2021.9778]
Rajagopalan, P., Hibar, D. P., Thompson, P. M. TREM2 and neurodegenerative disease. (Letter) New Eng. J. Med. 369: 1565-1567, 2013. [PubMed: 24131186] [Full Text: https://doi.org/10.1056/NEJMc1306509]
Reitz, C., Mayeux, R. TREM2 and neurodegenerative disease. (Letter) New Eng. J. Med. 369: 1564-1565, 2013. [PubMed: 24131184] [Full Text: https://doi.org/10.1056/NEJMc1306509]
Stefansson, H., Walters, G. B., Sveinbjornsson, G., Tragante, V., Einarsson, G., Helgason, H., Sigurdsson, A., Beyter, D., Snaebjarnarson, A. S., Ivarsdottir, E. V., Thorleifsson, G., Halldorsson, B. V., and 58 others. Homozygosity for R47H in TREM2 and the risk of Alzheimer's disease. New Eng. J. Med. 390: 2217-2219, 2024. [PubMed: 38899702] [Full Text: https://doi.org/10.1056/NEJMc2314334]