Mutations

TREM2 R47H

Overview

Pathogenicity: Alzheimer's Disease : Risk Modifier, Frontotemporal Dementia : Possible Risk Modifier, Parkinson's Disease : Possible Risk Modifier, Amyotrophic Lateral Sclerosis : Possible Risk Modifier
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's Disease
Reference Assembly: GRCh37 (105)
Position: Chr6:41129252 G>A
dbSNP ID: rs75932628
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CGC to CAC
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2
Research Models: 13

Findings

This variant was first linked to AD in 2013. Since then a number of studies have confirmed an association with risk of AD in European populations. The level of risk is about the same as one copy of the APOE E4 allele. This association has not been found in other populations, including African-Americans and Chinese subjects. In some populations, this variant may also influence the clinical presentation or rate of progression of the disease. Whether the R47H variant is a risk modifier for other neurodegenerative diseases remains uncertain.

Alzheimer's disease: Genetic association

In 2013, two groups independently identified this variant as a significant risk modifier for late-onset Alzheimer’s disease. In a discovery series composed of subjects of European or North American descent, one research group found the R47H variant in 22 of 1,091 AD cases and five of 1,105 controls (odds ratio: 4.5; p < 0.001). They then confirmed the association between the R47H variant and AD in a replication series of 1,887 cases and 4,961 controls (odds ratio: 4.59; p = 9.94×10−7). Meta-analysis of the summary statistics of several imputed genome-wide association studies provided further support for this association (Guerreiro et al., 2013).

Simultaneously, another group reported that the R47H variant significantly increased the risk of AD in Icelanders (3,550 AD and 8,888 control subjects over the age of 85; odds ratio: 2.92) and in a replication cohort composed of subjects from Germany, the Netherlands, Norway, and the United States (odds ratio: 2.83; p = 0.002) (Jonsson et al., 2013).

The association between the R47H variant and AD in populations of European descent was subsequently confirmed in multiple additional studies (Benitez et al., 2013; Finelli et al., 2015; Ghani et al., 2016; Gonzalez Murcia et al., 2013; Hooli et al., 2014; Jin et al., 2014; Pottier et al., 2013; Rosenthal et al., 2015; Ruiz et al., 2014; Sims et al., 2017; Slattery et al., 2014). Although the reported odds ratios varied, taken together, the results of these studies suggest that, in people of European ancestry, the risk conferred by the R47H allele is similar to that conferred by one copy of the ApoE4 allele.

Conversely, the R47H variant was not significantly associated with AD risk in an African-American cohort (Jin et al., 2015). Similarly, four studies failed to detect the R47H variant in Chinese subjects (total 2,558 AD, 2,708 controls; Jiao et al., 2014; Ma et al., 2014; Wang et al., 2017; Yu et al., 2014). In one study of Japanese subjects (2,190 AD, 2,498 controls), the R47H variant was extremely rare (minor allele frequency <0.006). While no association was found with AD in this study, the authors indicate that a larger sample size will be required to rule out an association with AD in the Japanese population (Miyashita et al., 2014).

Alzheimer's disease: Clinical phenotype

As yet, too few R47H carriers have been studied to draw conclusions regarding the influence of the R47H variant on the clinical presentation and/or progression of AD. In a study of Spanish AD patients (nine heterozygous R47H carriers, 48 noncarriers), R47H carriers showed apraxia, psychiatric symptoms, and Parkinsonian signs more frequently than noncarriers (Luis et al., 2014). However, two other studies reported similar clinical presentations in R47H carriers (12 carriers in each study), and noncarriers (Korvatska et al., 2015; Slattery et al., 2014). Similarly, there is disagreement as to whether the R47H variant affects age of symptom onset: One study found that R47H carriers had a significantly earlier age of onset (55 years vs. 62 years, 12 R47H carriers, 551 noncarriers) (Slattery et al., 2014), but a second study found no effect of the variant (25 R47H carriers, 1,253 noncarriers) (Rosenthal et al., 2015). In a North American family with late-onset AD, carriers had a shorter disease duration (6.7 vs. 11 years) (Korvatska et al., 2015).

The effect of the R47H variant has also been studied in asymptomatic individuals. Elderly (80–100 years of age) non-demented carriers of the R47H variant exhibited poorer cognitive function than noncarriers (Jonsson et al., 2013). However, there was no significant association between R47H carrier status and cognitive function or decline in a cohort of middle-aged participants in the Wisconsin Registry for Alzheimer’s Prevention (mean age approximately 50 years at baseline, 60 years at follow-up) (Engelman et al., 2014). Within this cohort, R47H carriers were more likely to have a parental history of AD, and families with an R47H carrier had a younger maternal age of symptom onset—on average, almost eight years younger than families who did not carry this variant.

Alzheimer's disease: Imaging and fluid biomarkers

As yet, few imaging studies have examined the effects on brain atrophy of the R47H allele. Volumetric MRI indicated more severe gray-matter loss in the orbitofrontal cortex and anterior cingulate cortex, with relative preservation of parietal lobes, in R47H carriers than in noncarriers among the Spanish AD subjects mentioned above. This finding persisted in a combined analysis of this Spanish cohort and a set of cognitively impaired ADNI subjects (seven MCI R47H carriers, two AD carriers; 20 MCI noncarriers, seven AD noncarriers) (Luis et al., 2014). It has also been reported that SNP rs9394721, a proxy for the R47H variant, is associated with accelerated temporal lobe atrophy and smaller hippocampal volumes in ADNI subjects (100 AD, 7 R47H carriers; 221 MCI, no R47H carriers; 157 healthy controls, no R47H carriers) (Rajagopalan et al., 2013). A second study confirmed the association between rs9394721 and hippocampal volume, but found that this association was significant only in non-demented elderly (Lupton et al., 2016).

A PiB-PET imaging study did not find a significant association of R47H with amyloid deposition (Rosenthal et al., 2015).

In terms of fluid biomarkers, it has been reported that AD and MCI carriers of the R47H variant have elevated levels of CSF tau compared with noncarriers (Lill et al., 2015). In addition, SNP rs9394721 was associated with elevated levels of CSF p-tau181 (Rajagopalan et al., 2013). Levels of soluble TREM2 in CSF were found to be higher in a small group of R47H carriers whose cognitive status ranged from normal (CDR 0) to demented (CDR >1), compared with cognitively normal subjects homozygous for the common TREM2 allele (Piccio et al., 2016).

Frontotemporal dementia: Genetic association

The R47H variant was reported to confer increased risk for frontotemporal dementia in a North American cohort (Rayaprolu et al., 2013) but not in several European cohorts (Borroni et al., 2014; Cuyvers et al., 2014; Lill et al., 2015; Ruiz et al., 2014; Slattery et al., 2014; Thelen et al., 2014).

ALS: Genetic association

One study reported that the R47H variant is associated with ALS in Caucasians (Cady et al., 2014), although two other studies failed to confirm this association (Lill et al., 2015; Rayaprolu et al., 2013). The R47H variant was not found in a cohort of 868 Chinese ALS patients (Chen et al., 2015).

Parkinson’s disease: Genetic association

Studies of the association of the R47H variant with Parkinson’s disease have reached conflicting conclusions. The R47H variant was found to increase the risk of Parkinson’s disease in Spanish and American cohorts (Benitez and Cruchaga, 2013). A study including North American, Irish, and Polish subjects supported this association (odds ratio 2.67, p = 0.026) (Rayaprolu et al., 2013). However, no association was seen in Icelanders (Jonsson et al., 2013) or in subjects from Denmark, Norway, or Sweden (Lill et al., 2015). A meta-analysis of these studies did not support an association between the R47H variant and the risk Parkinson’s disease in individuals of European descent (8,311 cases, 79,983 controls; odds ratio 1.36, p = 0.08, “genome-wide suggestive” significance threshold” of p = 10-4) (Lill et al., 2015). Subsequently, no association between the R47H variant and Parkinson’s risk was found in a German cohort, nor in a mega-analysis that included the data from the German subjects as well as data from the studies of Lill et al., Benitez and Cruchaga, and Rayaprolu et al. (6,402 cases, 7,147 controls; odds ratio 1.19, p = 0.49) (Mengel et al., 2016). Analysis of a large European GWAS data set (13,708 cases, 95,282 controls) also failed to support an association between the variant and PD (Liu et al., 2016). In four studies investigating the influence of TREM2 variants on Parkinson’s risk in Chinese cohorts, the R47H variant was found in only one of a total of 1,546 patients and in none of 2,011 controls, confirming the rarity of this variant among Chinese (Chen et al., 2015; Feng et al., 2014; Li et al., 2016; Tan et al., 2016).

Essential tremor: Genetic association

A significant association between the R47H variant and essential tremor was found in a Spanish cohort, but not in Italian, German, North American, or Taiwanese populations studied by the same group (Ortega-Cubero et al., 2015).

Lewy body dementia: Genetic association

The R47H variant was not found to be associated with Lewy body dementia in Caucasians (Walton et al., 2016).

Neuropathology

Published reports to date suggest that AD patients heterozygous for the R47H variant generally display typical AD pathology, but that there may be some subtle differences compared with patients with the common allele.

Autopsy results showed higher neuritic plaque densities in the brains of AD patients carrying the R47H allele compared with those with the common allele (Roussos et al., 2015). Brains from AD patients carrying the R47H variant showed reduced microglial coverage of amyloid plaques and more severe plaque-associated neuritic dystrophy (Yuan et al., 2016), as well as increased accumulation of autophagosomes in microglia, compared with specimens from patients who did not harbor this variant (Ulland et al., 2017). These histological changes are similar to those observed in APP transgenic mice with genetic deletion of TREM2 (Yuan et al., 2016; Ulland et al., 2017). In one study, levels of the microglial marker Iba1 (ionized calcium-binding adapter molecule 1) was found to be decreased in AD, and this decrease was more pronounced in R47H carriers (Korvatska et al., 2015).

More frequent α-synucleinopathy was observed in brains of R47H carriers (Korvatska et al., 2015).

Neuropathological findings from one AD patient homozygous for the R47H variant have been described (Slattery et al., 2014). This patient exhibited pronounced frontal atrophy, like that seen in Nasu-Hakola disease (NHD), but not the white-matter abnormalities typical of NHD.

Five sporadic Creutzfeldt-Jakob Disease (sCJD) patients carrying the R47H variant reportedly exhibited “classical” CJD neuropathology, with Aβ or tau pathology also present in three of these patients (Slattery et al., 2014).

Biological Effect

The R47H variant has been reported to exhibit subtle changes in conformation and stability as compared with the common variant (Kober et al., 2017). This variant does not seem to affect cell-surface expression (Kleinberger et al., 2014; Wang et al., 2015), although increased lysosomal degradation of this variant has been reported (Yin et al., 2015).

A major effect of the arginine-to-histidine amino acid change is to impair TREM2 ligand binding (Atagi et al., 2015; Bailey et al., 2015; Kober et al., 2017; Yeh et al., 2016).

Various heterologous expression systems have been used to assess the functional effects of the variant. HEK293 cells expressing the R47H variant showed reduced uptake of lipoprotein ligands (Yeh et al., 2016), fluorescently conjugated latex beads (Kleinberger et al., 2014), and aggregated Aβ42 (Kleinberger et al., 2014), compared with cells expressing the common TREM2 variant, although phagocytosis of pHrodo-labeled E. Coli did not differ between the two variants (Kleinberger et al., 2014). In comparison with transfection with the common TREM2 variant, transfection of BV2 cells (microglial cell line) with the R47H variant led to reduced uptake of fluorescently labeled beads and to reduced expression of pro-inflammatory cytokines in response to LPS stimulation (Yin et al., 2015). RAW264.7 macrophage cells expressing wild-type TREM2 exhibited sustained (least 60 minutes) signaling in response to receptor activation, while cells expressing the R47H variant exhibited only transient (10 minutes) signaling (Kober et al., 2017). Finally, the R47H mutation reduced activation in response to lipid ligands in 2B4 T cells (Wang et al., 2015; Song et al., 2017).

Soluble TREM2 (sTREM2) is produced by proteolytic processing of the protein. R47H sTREM2 was slightly less effective than wild-type sTREM2 in stimulating microglial production of the pro-inflammatory cytokines IL-1β, IL-6, TNFα and promoting microglial survival after trophic factor (GM-CSF) withdrawal (Zhong et al., 2017).

Research Models

Transgenic mice that express human TREM2 in the absence of mouse Trem2 have been created to study the effects of TREM2 variants in vivo. Observations in these animals thus far suggest that the R47H variant leads to partial loss of TREM2 function. Compared to animals expressing the common variant, amyloid plaque-bearing mice (5XFAD) that express R47H TREM2 have fewer plaque-associated microglia, express fewer TREM2-dependent activation markers, and show less binding of sTREM2 to neurons and amyloid plaques (Song et al., 2018).

Multiple mouse models also have been created in which the R47H point mutation was knocked into the endogenous mouse Trem2 gene (R47H KI (Haass)R47H KI (JAX), R47H KI (Lamb/Landreth)).  In all of these models, introduction of the R47H mutation resulted in decreased expression of Trem2 (Cheng-Hathaway et al., 2018; Xiang et al., 2018). Lower Trem2 expression in R47H knock-in mice has been traced to aberrant splicing of the mutant allele, which introduces a premature stop codon and could promote nonsense-mediated decay (Xiang et al., 2018). The R47H mutation does not, however, induce mis-splicing or reduce expression of human TREM2 (Xiang et al., 2018; for discussion on extrapolating findings from R47H knock-in mice to humans, see Sept 2018 news).

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References

Research Models Citations

  1. TREM2, humanized (common variant) X 5XFAD
  2. TREM2, humanized (R47H) X 5XFAD
  3. Trem2 R47H KI (Haass)
  4. Trem2 R47H KI (JAX)
  5. Trem2 R47H KI (Lamb/Landreth)

News Citations

  1. Model Morass? R47H Mutation Scuttles TREM2 Expression in Mice, Not People

Paper Citations

  1. . Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J Exp Med. 2018 Mar 5;215(3):745-760. Epub 2018 Jan 10 PubMed.
  2. . The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease. Mol Neurodegener. 2018 Jun 1;13(1):29. PubMed.
  3. . The Trem2 R47H Alzheimer's risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans. Mol Neurodegener. 2018 Sep 6;13(1):49. PubMed.
  4. . TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
  5. . Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):107-16. Epub 2012 Nov 14 PubMed.
  6. . TREM2 is associated with the risk of Alzheimer's disease in Spanish population. Neurobiol Aging. 2013 Jun;34(6):1711.e15-7. Epub 2013 Feb 5 PubMed.
  7. . TREM2 analysis and increased risk of Alzheimer's disease. Neurobiol Aging. 2015 Jan;36(1):546.e9-13. Epub 2014 Aug 27 PubMed.
  8. . Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer's disease data set. Neurobiol Aging. 2016 Jun;42:217.e7-217.e13. Epub 2016 Mar 21 PubMed.
  9. . Assessment of TREM2 rs75932628 association with Alzheimer's disease in a population-based sample: the Cache County Study. Neurobiol Aging. 2013 Dec;34(12):2889.e11-3. Epub 2013 Jul 12 PubMed.
  10. . The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk. Neurology. 2014 Oct 7;83(15):1353-8. Epub 2014 Sep 3 PubMed.
  11. . Coding variants in TREM2 increase risk for Alzheimer's disease. Hum Mol Genet. 2014 Nov 1;23(21):5838-46. Epub 2014 Jun 4 PubMed.
  12. . TREM2 R47H variant as a risk factor for early-onset Alzheimer's disease. J Alzheimers Dis. 2013;35(1):45-9. PubMed.
  13. . More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer's disease risk. Neurobiol Aging. 2015 Aug;36(8):2443.e21-6. Epub 2015 Apr 25 PubMed.
  14. . Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia. Neurobiol Aging. 2014 Feb;35(2):444.e1-4. Epub 2013 Sep 13 PubMed.
  15. . R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia. Alzheimers Dement. 2014 Nov;10(6):602-608.e4. Epub 2014 Aug 23 PubMed.
  16. . TREM2 is associated with increased risk for Alzheimer's disease in African Americans. Mol Neurodegener. 2015 Apr 10;10:19. PubMed.
  17. . Investigation of TREM2, PLD3, and UNC5C variants in patients with Alzheimer's disease from mainland China. Neurobiol Aging. 2014 Oct;35(10):2422.e9-2422.e11. Epub 2014 May 1 PubMed.
  18. . Association study of TREM2 polymorphism rs75932628 with late-onset Alzheimer's disease in Chinese Han population. Neurol Res. 2014 Oct;36(10):894-6. Epub 2014 Apr 13 PubMed.
  19. . Lack of association between triggering receptor expressed on myeloid cells 2 polymorphism rs75932628 and late-onset Alzheimer's disease in a Chinese Han population. Psychiatr Genet. 2018 Feb;28(1):16-18. PubMed.
  20. . Triggering receptor expressed on myeloid cells 2 variant is rare in late-onset Alzheimer's disease in Han Chinese individuals. Neurobiol Aging. 2014 Apr;35(4):937.e1-3. Epub 2013 Oct 11 PubMed.
  21. . Lack of genetic association between TREM2 and late-onset Alzheimer's disease in a Japanese population. J Alzheimers Dis. 2014;41(4):1031-8. PubMed.
  22. . Frontobasal gray matter loss is associated with the TREM2 p.R47H variant. Neurobiol Aging. 2014 Dec;35(12):2681-2690. Epub 2014 Jun 17 PubMed.
  23. . R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study. JAMA Neurol. 2015 Aug;72(8):920-7. PubMed.
  24. . Investigation of triggering receptor expressed on myeloid cells 2 variant in the Wisconsin Registry for Alzheimer's Prevention. Neurobiol Aging. 2014 Jun;35(6):1252-4. Epub 2013 Nov 20 PubMed.
  25. . TREM2 and neurodegenerative disease. N Engl J Med. 2013 Oct 17;369(16):1565-7. PubMed.
  26. . The effect of increased genetic risk for Alzheimer's disease on hippocampal and amygdala volume. Neurobiol Aging. 2016 Apr;40:68-77. Epub 2016 Jan 11 PubMed.
  27. . The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease. Alzheimers Dement. 2015 Dec;11(12):1407-1416. Epub 2015 Apr 30 PubMed.
  28. . Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016 Jun;131(6):925-33. Epub 2016 Jan 11 PubMed.
  29. . TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. Mol Neurodegener. 2013 Jun 21;8:19. PubMed.
  30. . Heterozygous TREM2 mutations in frontotemporal dementia. Neurobiol Aging. 2014 Apr;35(4):934.e7-10. Epub 2013 Oct 16 PubMed.
  31. . Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia. Neurobiol Aging. 2014 Mar;35(3):726.e11-9. Epub 2013 Oct 9 PubMed.
  32. . Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes. Neurobiol Aging. 2014 Nov;35(11):2657.e13-2657.e19. Epub 2014 Jun 20 PubMed.
  33. . TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol. 2014 Apr;71(4):449-53. PubMed.
  34. . Assessment of TREM2 rs75932628 association with amyotrophic lateral sclerosis in a Chinese population. J Neurol Sci. 2015 Aug 15;355(1-2):193-5. Epub 2015 May 16 PubMed.
  35. . TREM2 and neurodegenerative disease. N Engl J Med. 2013 Oct 17;369(16):1567-8. PubMed.
  36. . TREM2 and neurodegenerative disease. N Engl J Med. 2013 Oct 17;369(16):1568-9. PubMed.
  37. . TREM2 rare variant p.R47H is not associated with Parkinson's disease. Parkinsonism Relat Disord. 2016 Feb;23:109-11. Epub 2015 Nov 25 PubMed.
  38. . Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson's Disease Susceptibility. Mol Neurobiol. 2016 Sep;53(7):4931-8. Epub 2015 Sep 14 PubMed.
  39. . Assessment of TREM2 rs75932628 association with Parkinson's disease and multiple system atrophy in a Chinese population. Neurol Sci. 2015 Oct;36(10):1903-6. Epub 2015 Jun 10 PubMed.
  40. . Triggering receptor expressed on myeloid cells 2 variants are rare in Parkinson's disease in a Han Chinese cohort. Neurobiol Aging. 2014 Jul;35(7):1780.e11-2. Epub 2014 Feb 5 PubMed.
  41. . Association study of TREM2 polymorphism rs75932628 with leucoaraiosis or Parkinson's disease in the Han Chinese population. BMJ Open. 2016 Jan 12;6(1):e009499. PubMed.
  42. . Genetic analysis of TREM2 variants in Chinese Han patients with sporadic Parkinson's disease. Neurosci Lett. 2016 Jan 26;612:189-192. Epub 2015 Dec 15 PubMed.
  43. . TREM2 R47H variant and risk of essential tremor: a cross-sectional international multicenter study. Parkinsonism Relat Disord. 2015 Mar;21(3):306-9. Epub 2014 Dec 24 PubMed.
  44. . TREM2 p.R47H substitution is not associated with dementia with Lewy bodies. Neurol Genet. 2016 Aug;2(4):e85. Epub 2016 Jul 14 PubMed.
  45. . The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia. Alzheimers Dement. 2015 Oct;11(10):1163-70. Epub 2014 Dec 9 PubMed.
  46. . TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron. 2016 May 18;90(4):724-39. PubMed.
  47. . TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. Cell. 2017 Aug 10;170(4):649-663.e13. PubMed.
  48. . Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. Elife. 2016 Dec 20;5 PubMed.
  49. . TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014 Jul 2;6(243):243ra86. PubMed.
  50. . TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015 Mar 12;160(6):1061-71. Epub 2015 Feb 26 PubMed.
  51. . Vps35-dependent recycling of Trem2 regulates microglial function. Traffic. 2016 Dec;17(12):1286-1296. Epub 2016 Nov 1 PubMed.
  52. . Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). J Biol Chem. 2015 Oct 23;290(43):26043-50. Epub 2015 Sep 15 PubMed.
  53. . The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E. J Biol Chem. 2015 Oct 23;290(43):26033-42. Epub 2015 Sep 15 PubMed.
  54. . TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron. 2016 Jul 20;91(2):328-40. PubMed.
  55. . Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement. 2017 Apr;13(4):381-387. Epub 2016 Aug 9 PubMed.
  56. . Soluble TREM2 induces inflammatory responses and enhances microglial survival. J Exp Med. 2017 Mar 6;214(3):597-607. Epub 2017 Feb 16 PubMed.

External Citations

  1. Sims et al., 2017

Further Reading

Protein Diagram

Primary Papers

  1. . TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
  2. . Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):107-16. Epub 2012 Nov 14 PubMed.

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