Variant of TREM2 Associated with the Risk of Alzheimer's Disease
Open accessAbstract
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.).
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GWAS and sequencing studies have found associations between AD and genes expressed in myeloid cells, including TREM2, ABCA7, and CD33.
“At the genetic level, GWAS and sequencing studies have found associations between AD and genes expressed in myeloid cells, including TREM2, ABCA7, and CD331,2,5,15–17.”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [15]
The Results report an association between a TREM2 variant and Alzheimer’s disease, and the Discussion identifies TREM2 in microglia and CD33 as a myeloid cell-surface receptor linked to Alzheimer’s disease by genomewide association studies. ABCA7 appears in a cited study’s title in the References, but the paper does not discuss its myeloid-cell expression; that part of the claim is not supported by this copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTREM2 and two novel rare coding variants, PLCG2 and ABI3, implicate innate immunity in AD pathophysiology.
“TREM2 (219, 300, 543) and two novel rare coding variants, PLCG2 and ABI3 , implicate innate immunity in AD pathophysiology (543), but whether these variants can influence vascular-inflammatory cross-talk contributing to AD pathophysiology remains unclear.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [300]
The Discussion links the TREM2 risk variant to microglial immune activity, supporting the TREM2 portion of the claim. The paper does not address PLCG2 or ABI3, so it cannot support the claim about those two variants. (LLM, conf=0.90)
Experimental — accuracy not yet measuredGWAS identified many AD risk genes related to the immune response and microglia, including phagocytosis genes such as CD33 and TREM2.
“Genome-wide association studies (GWAS) identified many AD risk genes related to the immune response and microglia, including those implicated in phagocytosis, such as CD33 and TREM24,5,6,7,8.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [8]
The Discussion reports Alzheimer’s risk variants in several inflammation-related genes, including CD33, and links TREM2 in microglia to phagocytosis. The Results report a genomewide association for a TREM2 variant. Our copy describes CD33 as a myeloid cell-surface receptor but does not establish its role in phagocytosis, so that part of the claim is unsupported. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPrior studies proposed that plaque-associated microglia compact amyloid plaques through receptors implicated in phagocytosis such as TREM2, AXL, and MER.
“Prior studies proposed that these cells compact amyloid plaques through receptors implicated in phagocytosis such as TREM214, (expressed on myeloid cells and associated to increased AD risk)14,8, AXL, and MER79.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [8]
The Discussion (page unavailable in our copy) says TREM2 is expressed on microglia and links its expression to amyloid phagocytosis near plaques. It does not say that TREM2 enables microglia to compact plaques. The AXL and MER portion carries a different citation and is not attributed to this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCoding alterations in TREM2 dramatically increase the risk of developing late-onset Alzheimer's disease (LOAD).
“Coding alterations in TREM2, a transmembrane glycoprotein expressed on myeloid lineage cells that modulates innate immune function [1], dramatically increase the risk of developing late-onset Alzheimer’s disease (LOAD) [2,3].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [3]
The Abstract Results report that one coding alteration, rs75932628-T (R47H), is associated with approximately threefold higher odds of Alzheimer’s disease. The Results section says no other TREM2 variant likely to affect protein function showed a nominally significant association, so this paper does not support the broader claim that coding alterations generally increase LOAD risk. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
PLCG2 is a downstream component of TREM2 signaling, an important microglial AD risk gene.
“PLCG2 has also been shown to be a downstream component of TREM2 signaling, an important microglial AD risk gene. 7 , 8”
From The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model (2022) · cites this paper as [8]
The Results identify a TREM2 variant associated with Alzheimer’s disease, and the Discussion says TREM2 is primarily expressed on microglia in the brain. The Discussion describes DAP12 in TREM2 signaling but does not identify PLCG2 as a downstream component. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe loss-of-function TREM2 variant R47H impairs microglial responses to Aβ and confers increased risk for AD.
“Moreover, the loss‐of‐function TREM2 variant R47H impairs microglial responses to Aβ and confers increased risk for AD.”
From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [38]
The Results establish that R47H is associated with increased Alzheimer’s disease risk. The Discussion proposes that R47H may reduce TREM2 activity and impair microglial clearance of amyloid, but does not establish that R47H is a loss-of-function variant or that it impairs microglial responses to Aβ. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTREM2 loss-of-function impairs microglial protective functions and worsens neuronal dystrophy.
“TREM2 loss‐of‐function impairs microglial protective functions and worsens neuronal dystrophy. 9 , 37 , 38 , 41 , 42 , 61”
From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [38]
The Discussion (page unavailable) reports that TREM2 knock-down reduces microglial phagocytosis of apoptotic neurons, supporting an impaired protective function. It does not report that TREM2 loss-of-function worsens neuronal dystrophy; its proposed link between reduced TREM2 activity and brain damage is explicitly tentative. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn AD, amyloid pathology induces the expression of TREM2 in microglia.
“In AD, amyloid pathology induces the expression of TREM2 in microglia. 36 , 37 , 38 , 39 , 40 , 41 , 60”
From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [38]
The Discussion (page not provided) reports that TREM2 expression in microglia was induced concomitantly with amyloid-plaque formation in APP transgenic mice. This supports an association, but does not establish that amyloid pathology causes TREM2 expression in people with Alzheimer’s disease. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRare coding variants in microglial genes such as TREM2 and PLCG2 are linked to Alzheimer's disease pathology.
“Human genetic studies have linked rare coding variants in microglial genes, such as TREM2, and more recently PLCG2 to Alzheimer’s disease (AD) pathology.”
From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [3]
The Results (Association of Variant with Alzheimer’s Disease; page unavailable) report that a rare coding variant in TREM2 is significantly associated with Alzheimer’s disease risk, and the Discussion identifies TREM2 as expressed in microglia. Our copy does not address PLCG2, so it supports the TREM2 part but not the full claim attributed to this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTREM2-R62H (AF = 0.0078) is more common in the Finnish population than the TREM2-R47H (AF = 0.00045) AD risk variant.
“The TREM2-R62H (AF = 0.0078) is more common in the Finnish population than the more widely known TREM2-R47H (AF = 0.00045) AD risk variant [15, 25].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [25]
The Results section identifies TREM2-R47H as an Alzheimer’s disease risk variant. It reports an allele frequency for Iceland, not Finland; our copy does not establish the Finnish frequencies, discuss R62H, or compare the two variants there (searched: R62H, Finnish, and the stated frequencies). (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn the brain, PLCG2 is predominantly microglial expressed.
“In the brain, PLCG2 is predominantly microglial expressed, positioning PLCγ2 within the same interaction network as TREM2—a notable AD risk gene (Andreone et al. 2020; Jonsson et al. 2013).”
From Alzheimer's Protection by <scp>PLCγ2</scp> Compacts Plaques, Redistributes Microglia, and Protects Synapses in <scp> <i>App</i> <sup> <i>NL</i> </sup> </scp> <sup> <i>‐G‐F</i> </sup> Mice (2026) · cites this paper as Jonsson et al. 2013
The Discussion (page unavailable) says TREM2, not PLCG2, is primarily expressed on microglia in the brain. The Results identify a TREM2 variant associated with Alzheimer’s disease risk, supporting that part of the citing sentence. Our copy does not establish predominant microglial expression of PLCG2 or an interaction network linking PLCγ2 to TREM2. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTREM2 deficiency leads to adverse phenotypes involving mostly the brain and the bones, manifesting more severely in humans than mice.
“TREM2 deficiency leads to adverse phenotypes involving mostly the brain and the bones, and manifesting more severely in humans than mice [42, 105]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [42]
The Discussion (page unavailable in our copy) links TREM2 loss-of-function mutations to a human disease affecting the brain and bones. It does not compare the severity of TREM2 deficiency in humans and mice, so that part of the claim is unsupported. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRecent genetic studies implicate inflammatory genes and pathways (CD33, TREM2, HLA-DRB5-DRB1) in late-onset disease pathology.
“Third, recent genetic studies implicate inflammatory genes and pathways (CD33, TREM2, HLA-DRB5-DRB1) in late-onset disease pathology (112–115).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [114]
The Results and Discussion (page not available in our copy) link a TREM2 variant to Alzheimer’s disease risk and discuss inflammation; the Discussion also reports an association for CD33. The paper does not address HLA-DRB5-DRB1, so it does not support the full gene list attributed to the citation group. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe risk of dementia for carriers of rare APOE variants was substantial, with effect sizes similar to those for ɛ4 and other rare variants in dementia risk genes such as TREM2.
“the risk of dementia for carriers of rare APOE variants was also substantial, with effect sizes similar to those for ɛ4 as well as other rare variants in dementia risk genes such as TREM2. 43”
From <i>APOE</i> and dementia – resequencing and genotyping in 105,597 individuals (2020) · cites this paper as [43]
The Results (Association with APOE ε4) report that the rare TREM2 variant rs75932628-T had an Alzheimer’s disease odds ratio similar to that of APOE ε4 (2.92 versus 3.08). The paper does not establish the claimed risk or effect sizes for carriers of rare APOE variants; it compares TREM2 with the ε4 allele. (LLM, conf=0.87)
Experimental — accuracy not yet measuredA rare variant of the TREM2 gene encoding p.Arg47His causes a 3-fold increase in the risk for late-onset Alzheimer's disease (LOAD).
“A rare variant of the TREM2 gene encoding p.Arg47His causes a 3-fold increase in the risk for late-onset Alzheimer's disease (LOAD).”
From Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease (2017) · cites this paper as [10]
The Results (Association of Variant with Alzheimer’s Disease; page not supplied) identify the rare TREM2 R47H variant and report an odds ratio of 2.92, approximately threefold. The paper establishes an association, however, and its Conclusions describe a possible mechanism rather than demonstrating that the variant causes the increase in risk. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRare variants in TREM2 are major genetic risk factors for AD.
“NGS allowed the identification of rare variants in TREM2 as major genetic risk factors for AD [39, 65].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [65]
The Results section reports that whole-genome sequencing identified a rare TREM2 variant, rs75932628-T, associated with substantially increased Alzheimer’s disease risk. The paper establishes this for one variant, not multiple TREM2 variants: it says no other potentially functional TREM2 variant showed a nominally significant association. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRecent sequencing studies identified a number of genes with rare variants associated with Alzheimer's disease.
“Recent sequencing studies identified a number of genes that have rare variants associated with AD9-11,18-24.”
From Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease (2017) · cites this paper as [9]
Nearly 30 late-onset Alzheimer's disease susceptibility loci are known, and risk is significantly polygenic.
“Nearly 30 LOAD susceptibility loci2-12 are known, and risk is significantly polygenic13.”
From Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease (2017) · cites this paper as [9]
Evidence for the previously reported TREM2 rare variant p.R47H was observed.
“We also observed evidence for the previously reported9,11 TREM2 rare variant p.R47H (Table 2).”
From Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease (2017) · cites this paper as [9]
Microglial TREM2 variants are partial loss of function with impaired transport of APOE-containing lipoproteins.
“Microglial TREM2 variants (300, 344) are partial loss of function with impaired transport of APOE-containing lipoproteins (633).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [300]
GWAS have identified multiple loci associated with AD, including variants in PICALM, CLU, ABCA7, SORL1, CR1, TREM2, and BIN1.
“Genome-wide association studies (GWAS) have identified multiple loci associated with AD including to name a few, variants in PICALM , CLU , ATP-binding cassette transporter A7 ( ABCA7 ), sortilin related receptor-1 ( SORL1 ), complement receptor 1 ( CR1 ), triggering receptor expressed on myeloid cells 2 ( TREM2 ), and bridging integrator 1 ( BIN1 ) genes (219, 236, 254, 300, 343, 344, 528, 543).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [300]
Some additional highly replicated AD risk genes include CR1, BIN1, and TREM2.
“Some additional highly replicated risk genes include CR1 , BIN1 , and TREM2 (94, 119, 219, 300, 344, 543).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [300]
TREM2 and CD33 are also Alzheimer's disease risk genes.
“In the brain, PLCγ2 is primarily expressed by microglia, where it serves as an important signaling node downstream of TREM2 and CD33 (19, 20), both also AD risk genes (21–23).”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [21]
Within the brain, PLCγ2 is primarily but not exclusively expressed in microglia, where it serves as an important signaling node downstream of TREM2 and CD33.
“Within the brain, PLCγ2 is primarily but not exclusively expressed in microglia, where it serves as an important signaling node downstream of TREM2 and CD33 [31, 32], both also AD risk genes [33–35].”
From PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain (2026) · cites this paper as [33]
TREM2 variants associate with an increased risk of AD.
“Importantly, TREM2 variants associate with an increased risk of AD [15, 25, 38–40].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [25]
PLCγ2 is positioned within the same interaction network as TREM2, a notable AD risk gene.
“In the brain, PLCG2 is predominantly microglial expressed, positioning PLCγ2 within the same interaction network as TREM2—a notable AD risk gene (Andreone et al. 2020; Jonsson et al. 2013).”
From Alzheimer's Protection by <scp>PLCγ2</scp> Compacts Plaques, Redistributes Microglia, and Protects Synapses in <scp> <i>App</i> <sup> <i>NL</i> </sup> </scp> <sup> <i>‐G‐F</i> </sup> Mice (2026) · cites this paper as Jonsson et al. 2013
The p.R47H variant (rs75932628) in TREM2 was independently identified by two research groups in 2013.
“The first well-known rare variant for AD is the p.R47H variant (rs75932628) in TREM2, which was independently identified by two research groups in 2013 [35, 36].”
From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [36]
The P522R PLCG2 coding variant (rs72824905) is downstream of TREM2.
“The Alzheimer's disease protective P522R PLCG2 coding variant (rs72824905) is downstream of TREM2, but how it confers disease protection is poorly understood.”
From Alzheimer's Protection by <scp>PLCγ2</scp> Compacts Plaques, Redistributes Microglia, and Protects Synapses in <scp> <i>App</i> <sup> <i>NL</i> </sup> </scp> <sup> <i>‐G‐F</i> </sup> Mice (2026) · cites this paper as Jonsson et al. 2013
The Discussion describes TREM2 signaling through DAP12, but does not identify PLCG2 or place the P522R variant downstream of TREM2. Searches for PLCG2, P522R, rs72824905, and the proposed pathway relationship found no passage addressing that claim in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredNeuroinflammation is a common feature of Alzheimer's disease, and GWAS have associated several immune-related genes with AD, including ABCA7, CD33, CLU, CR1, MS4A, and TREM2.
“Neuroinflammation is a common feature of AD9 and GWAS have associated several immune-related genes with AD including ABCA7, CD33, CLU, CR1, MS4A10, 11 and recently TREM2.12, 13”
From Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease (2015) · cites this paper as [13]
Stage 1 discovery meta-analysis produced 12 loci with genome-wide significance (P ≤ 5 × 10−8), all previously described.
“The Stage 1 discovery meta-analysis produced 12 loci with genome-wide significance (P ≤ 5 × 10−8) (Table 1), all of which are previously described1,4–11.”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [7]
Three signals not initially described in the initial IGAP GWAS were the rare R47H TREM2 coding variant, ECHDC3, and ACE.
“Three other signals were not initially described in the initial IGAP GWAS: the rare R47H TREM2 coding variant previously reported by others7,8,14; ECHDC3 (rs7920721; NC_000010.10: g.11720308A>G), which was recently identified as a potential genome-wide-significant Alzheimer’s disease risk locus in several studies15–17, and ACE (rs138190086; NC_000017.10: g.61538148G>A)”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [7]
Increased risk of developing Alzheimer disease is significantly associated with rare variants of innate immune receptors expressed in microglia, including TREM2, CD33, and CR1.
“an increased risk for developing AD is significantly associated with rare variants of innate immune receptors expressed in microglia, including TREM2 (107, 108), CD33 (109), and complement receptor 1 (CR1) (110)”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [108]
The rare R47H variant of TREM2 is associated with increased Alzheimer disease risk and impairs TREM2 binding to many phospholipid ligands.
“A rare arginine 47 histidine (R47H) variant of TREM2 is associated with an increased risk for AD (107, 108). This variant impairs binding of TREM2 to many phospholipid ligands (114, 125).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [108]
TREM2 is a pivotal risk factor for LOAD and is associated with tau pathology.
“TREM2, a pivotal risk factor for LOAD [119, 120], is associated with tau pathology.”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [119]
The TREM2 R47H mutation increases the risk of Alzheimer's disease approximately threefold.
“The TREM2 mutation most clearly associated with AD (R47H, carried by <0.5% of most populations) increases the risk of AD approximately threefold (Guerreiro et al., 2013; Jonsson et al., 2013).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Jonsson et al., 2013
Rare genetic variants associated with Alzheimer's disease have implicated microglia in determining the risk of Alzheimer's disease.
“rare genetic variants associated with AD (found by gene sequencing or exome array) have also implicated microglia in determining the risk of AD (Guerreiro et al., 2013; Jonsson et al., 2013; Sims et al., 2017).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Jonsson et al., 2013
Trem2 mutations are associated with a 3.0- to 4.5-fold increased AD risk, almost as high as that associated with ApoE ε4.
“Mutations in triggering receptor expressed on myeloid cells 2 (Trem2) were associated with a 3.0- to 4.5-fold increased AD risk, almost as high as that associated with ApoE ε434,35.”
From Microglia in neurodegeneration (2018) · cites this paper as [35]
The R47H variant of TREM2 is associated with a 2- to 4-fold increased risk for the development of AD.
“GWAS showed that the R47H variant of TREM2 was associated with a 2- to 4-fold increased risk for the development of AD.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [164]
A proteomic relationship between Alzheimer's disease and FTD is supported by TREM2 mutations causing microglial dysfunction and leading to Alzheimer's disease, and PGRN mutations causing microglial dysfunction and leading to FTD.
“A proteomic relationship between AD and FTD is supported by the fact that mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) protein cause microglial dysfunction and lead to AD39,40, whereas mutations in the progranulin (PGRN) protein also cause microglial dysfunction and lead to FTD41–43.”
Genes linked to early-onset AD risk that are expressed primarily in microglia include TREM2, MS4A, ABCA7, ApoE4, CD33, PU.1, and BIN1.
“Genetic studies show that a number of genes that have been linked to early-onset AD risk are expressed primarily in microglia.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [126]
A protective role for TREM2 appears to be the predominant biologic effect, given that TREM2 mutations are associated with increased risk of Alzheimer disease in humans.
“Given that TREM2 mutations are associated with increased risk of AD in humans126,176,177, a protective role for this receptor appears to be the predominant biologic effect.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [126]
A rare TREM2 mutation (R47H) is associated with a substantial increase in the risk of developing Alzheimer disease.
“A rare mutation of TREM2 (R47H) is associated with a substantial increase in the risk of developing AD126.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [126]
Genetic studies have identified several immune gene polymorphisms as risk factors for Alzheimer's disease, confirming the importance of microglia-mediated neuroinflammation in neurodegeneration.
“The importance of microglia-mediated neuroinflammation in neurodegeneration has been confirmed by genetic studies that identified several immune gene polymorphisms as risk factors for AD [5–8].”
From Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease (2018) · cites this paper as [7]
TREM2 is a potent risk gene for late-onset Alzheimer's disease.
“We and others identified the microglial gene TREM2 as a potent risk gene for late-onset disease (Guerreiro et al., 2013; Jonsson et al., 2013)”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Jonsson et al., 2013
A decade of GWAS projects for Alzheimer's disease has provided insights into the progression of late-onset Alzheimer's disease, particularly the dependence on the innate immune system, with the identification of genes such as TREM2 and SPI1/PU.1.
“A decade of GWAS projects for Alzheimer’s disease has provided key and initially surprising insights into the progression of late-onset Alzheimer’s disease, particularly the dependence on the innate immune system, with the identification of genes such as TREM2 and SPI1/PU.1”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Jonsson et al., 2013
Rare TREM2 variants increase risk for late-onset Alzheimer's disease.
“Rare variants in the microglia-enriched gene TREM2 confer high risk for LOAD (Guerreiro et al., 2013a; Jonsson et al., 2013; Sims et al., 2017).”
From Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models (2018) · cites this paper as Jonsson et al., 2013
Variants in TREM2 are risk factors for late-onset Alzheimer's disease.
“identified variants in TREM2 (“triggering receptor expressed on myeloid cells 2”) as risk factors for LOAD [24, 25]”
From Microglial dysfunction in brain aging and Alzheimer's disease (2014) · cites this paper as [25]
Missense mutations in TREM2 lead to a significant risk of developing AD.
“Missense mutations in TREM2 lead to a significant risk of developing AD (Jonsson et al., 2013; Meyer-Luehmann and Prinz, 2015).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Jonsson et al., 2013
The R47H variant in TREM2 confers elevated risk for AD.
“One of the most well-studied rare variants that confers elevated risk for AD is the R47H variant in TREM2 [131, 132].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [131]
Variants of the microglial TREM2 gene increase susceptibility to late-onset AD with an odds ratio similar to that of APOEε4.
“In addition, two groups of investigators independently identified variants of the microglial TREM2 gene that increase susceptibility to LOAD with an odds ratio similar to that of APOEε4 [56–58].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [57]
Variants of the microglial TREM2 gene increase the risk of sporadic AD by approximately 3- to 5-fold.
“Variants of the microglial TREM2 gene have been found to increase the risk of sporadic AD by approximately 3- to 5-fold [56, 57].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [57]
The R47H variant of TREM2 has an effect size for increased Alzheimer's disease risk comparable to the APOEε4 allele, around a 3-fold increased risk.
“The risk from this variant has a comparable effect size with the APOEε4 allele (around 3-fold increased AD risk; 4,19–22).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [4]
Variants in TREM2, including the R47H variant, are associated with increased risk of Alzheimer's disease.
“Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer’s disease (AD).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [4]
Data from human genetics, particularly with respect to the hypomorphic R47H allele of TREM2 that strongly increases risk for AD, provide strong evidence for a protective role for microglia.
“Data from human genetics, particularly with respect to the hypomorphic R47H allele of TREM2 that strongly increases risk for AD (32, 33, 102), provide strong evidence for a protective role for microglia.”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [33]
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“The discovery that rare coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with a twofold to fourfold increased risk for developing sporadic, lateonset AD further implicates the role of microglia in AD (6, 7).”
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“As an age-related neurodegenerative disease, AD is divided into two subtypes according to the age of onset: early-onset AD (EOAD, 65 years) and late-onset AD (LOAD, ≥ 65 years).”
BackgroundInfluentialDisease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease
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“This is one of the fastest growing fields of disease genetics and has had some initial success (Guerreiro et al. 2013; Jonsson et al. 2013).”
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- Authors
- 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., Giegling, I., Andreassen, O. A., Engedal, K., Ulstein, I., Djurovic, S., Ibrahim-Verbaas, C., Hofman, A., Ikram, M. A., van Duijn, C. M., Thorsteinsdottir, U., Kong, A., & Stefansson, K.
- Affiliations
- deCODE Genetics (Iceland) (IS)
- University of Tübingen (DE)
- Emory University (US)
- Martin Luther University Halle-Wittenberg (DE)
- Goethe University Frankfurt (DE)
- Oslo University Hospital (NO)
- Norwegian National Centre for Ageing and Health (NO)
- Erasmus MC (NL)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2013-01-10
- Volume
- 368
- Issue
- 2
- Pages
- 107-116
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3677583
- OpenAlex
- W2128613449
- Cited by
- 2,558
- References
- 51
- Citations by year
- 2026: 133 · 2025: 160 · 2024: 201 · 2023: 202 · 2022: 211 · 2021: 233 · 2020: 232 · 2019: 192 · 2018: 220 · 2017: 168 · 2016: 151 · 2015: 167 · 2014: 150 · 2013: 129 · 2012: 6
- FWCI
- 96.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Hirsla (Landspítali University Hospital) (submittedVersion, other-oa)
- Funders
- National Institute on Aging (U01AG006781, P50AG025688, U24AG021886)
- National Human Genome Research Institute (U01HG004438, U01HG004610, U01HG006375, U01HG004603)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- TREM2, Alzheimer's disease, late-onset Alzheimer's disease, genetic risk, rare variants, cognitive function, neuroinflammation, Icelandic population, replication
- MeSH terms
- Aged, 80 and over, Alzheimer Disease, Cognition, Heterozygote, Humans, Iceland, Membrane Glycoproteins, Receptors, Immunologic, Risk Factors, Genetic Variation, Case-Control Studies, Sequence Analysis, DNA, Mutation, Missense, Polymorphism, Single Nucleotide, Apolipoprotein E4, Genotyping Techniques
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