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/hg19
Position: Chr6:41129252 G>A
dbSNP ID: rs75932628
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2
Research Models: 25

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 13 Sep 2018

Paper Citations

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External Citations

1. Sims et al., 2017

Further Reading