TREM2 Variants in Alzheimer's Disease
Open accessAbstract
BACKGROUND: Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS: We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS: We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).
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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 [219]
The introduction identifies CLU, PICALM, CR1, BIN1, and ABCA7 as genes implicated by genome-wide association studies. The Methods and Results describe TREM2 as identified through sequencing, with an imputed GWAS meta-analysis confirming its association—not identifying it. The cited paper does not identify SORL1 among the GWAS loci it discusses. (LLM, conf=0.88)
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 [219]
The Discussion links rare TREM2 variants to Alzheimer’s disease risk and describes TREM2’s role in microglial immune and inflammatory responses. Our copy does not identify PLCG2 or ABI3 as Alzheimer’s-associated rare coding variants; searches for both genes found no relevant passage. The citation therefore supports the TREM2 portion, but not the claim about the other two genes. (LLM, conf=0.91)
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 [7]
The introductory passage lists CD33 among Alzheimer’s risk loci identified by GWAS, and the Discussion links TREM2 in microglia to phagocytosis. But the Methods (Study Design) say this paper identified the TREM2 variants through exome or full-genome sequencing; GWAS data were used afterward to confirm an association, not to identify TREM2 as the claim states. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPLCG2 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 [7]
The Discussion identifies TREM2 as a signaling receptor and reports that rare TREM2 variants increase Alzheimer’s disease risk; the Results locate TREM2 in microglia around amyloid plaques. But the paper does not identify PLCG2 as a downstream component of TREM2 signaling; its Discussion names TYROBP as a component of the receptor-signaling complex. (LLM, conf=0.88)
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 [2]
The Abstract Results and Conclusions report an association between rare TREM2 variants and Alzheimer’s disease, and the Discussion places TREM2 in microglial responses. The paper does not report a PLCG2 variant association, so it supports only the TREM2 part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Several AD risk-increasing variants in TREM2, such as R47H and R62H, have been recognized.
“In TREM2 gene, several AD associated risk increasing variants have been recognized, such as R47H and R62H [1, 13–15].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [15]
The Results report that several TREM2 variants are associated with Alzheimer’s disease and identify R47H as the most strongly associated. A search for R62H found no passage addressing that variant, so this source does not support the R62H example. (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 [15]
The Results section identifies TREM2-R47H as an Alzheimer’s disease risk variant. The Methods section reports an R47H minor allele frequency of 0.003 from the 1000 Genomes Project, but the copy does not report R62H or either stated frequency in the Finnish population. It therefore does not support the claimed Finnish frequency comparison. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAD-associated TREM2 risk variants - including p.H157Y, p.R98W, p.D87N, p.T66M, p.R62H, p.R47H, p.Y38C and p.Q33X - affect TREM2 function by various mechanisms.
“AD-associated TREM2 risk variants – including p.H157Y, p.R98W, p.D87N, p.T66M, p.R62H, p.R47H, p.Y38C and p.Q33X [6, 43] – affect TREM2 function by various mechanisms”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [6]
The Results identify several listed variants in Alzheimer’s cases and report a strong association for R47H. They describe Q33X as almost certainly causing loss of function and propose some loss of function for T66M and Y38C; the Discussion suggests reduced TREM2 function more broadly. These passages do not establish distinct mechanisms for the listed variants, and the passages found do not address R62H. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe most characterised variant of TREM2 (p.R47H) shows defects in ligand binding, which impacts the ability of TREM2 to recognise damage, and induce microglial changes, resulting in a dampened response to pathological insults such as Aβ deposition.
“The most characterised variant of TREM2 (p.R47H) shows defects in ligand binding [6, 37, 38, 97], which impacts the ability of TREM2 to recognise damage, and induce microglial changes, resulting in a dampened response to pathological insults such as Aβ deposition.”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [6]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredMost of the genes associated with the ~40 loci identified by genome-wide association (GWA) analysis or by rare variant sequencing studies are expressed in glial cells (e.g., APOE, TREM2, BIN1, CD33, INPP5D, CTSB, CTSD, and PICALM).
“Most of the genes associated with the ~40 loci identified by genome-wide association (GWA) analysis or by rare variant sequencing studies are expressed in glial cells (e.g., APOE, TREM2, BIN1, CD33, INPP5D, CTSB, CTSD, and PICALM).”
From The Major Risk Factors for Alzheimer’s Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques (2019) · cites this paper as Guerreiro et al., 2013
The Results (page unavailable) report Trem2 expression in microglia, and the paper links TREM2 variants to Alzheimer’s disease. Its introductory discussion lists several other Alzheimer’s-associated genes, but it does not establish that most genes at approximately 40 loci are expressed in glial cells or document glial expression for the other listed examples. (LLM, conf=0.89)
Experimental — accuracy not yet measuredTREM2 is one of the strongest risk factors for AD, and evidence suggests that TREM2 acts to recognize Aβ pathology and direct microglial responses toward the pathology.
“For instance, TREM2 is one of the strongest risk factors for AD, and evidence suggests that TREM2 acts to recognize Aβ pathology and direct microglial responses toward the pathology (Guerreiro et al., 2013; Zhou et al., 2020).”
From β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease (2024) · cites this paper as Guerreiro et al., 2013
The Abstract and Results report that rare TREM2 variants significantly increase Alzheimer’s disease risk. The Discussion reports TREM2 expression in microglia around amyloid plaques and describes it as a possible gateway for microglial responses. It does not establish that TREM2 itself recognizes Aβ pathology or directly guides microglia toward it. (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 [113]
The Discussion (page not specified) links TREM2 to immune and inflammatory signaling and reports that its variants predispose to Alzheimer’s disease. The introductory passage (page not specified) lists CD33 among genes implicated by studies of late-onset disease. Our copy does not identify HLA-DRB5-DRB1, so it does not support that part of the sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRecent genome-wide association studies of LOAD identified several common variants of new genes, but with the exception of variants of triggering receptor expressed on myeloid cells 2, no rare variants were identified.
“These studies have identified several common variants of several new genes to be associated with LOAD, but, with the exception of variants of triggering receptor expressed on myeloid cells 2, no rare variants were identified (49,50).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [50]
The introduction lists several loci identified by genome-wide association studies of late-onset Alzheimer’s disease, and the Conclusions identify rare TREM2 variants associated with Alzheimer’s risk. However, the Methods say the rare TREM2 variant was excluded from previously reported GWAS and was investigated here using sequencing and imputed GWAS data. The paper does not establish the broader claim that no other rare variants had been identified. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGWAS 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 [16]
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 [11]
Recent 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 [11]
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 [11]
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 [219]
TREM2 genetic variants increase SAD risk.
“Another, more recently identified risk factor is the triggering receptor expressed on myeloid cells 2 (TREM2), where genetic variants also increase SAD risk [145].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [145]
Polymorphisms in the R47H allele of the TREM2 gene are a strong genetic risk factor for the development of Alzheimer's disease, though their impact on microglial function remains unclear.
“Polymorphisms in the R47H allele of the TREM2 gene have recently been identified as a strong genetic risk factor for the development of AD,13 though the actual impact of these polymorphisms on microglial function remain unclear.”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [13]
Coding 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 [2]
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 [22]
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 [34]
TREM2 is a transmembrane receptor expressed on myeloid cells and an important susceptibility gene for AD.
“TREM2 is a transmembrane receptor expressed on the membrane of myeloid cells and an important susceptibility gene for AD [5].”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [5]
Mutations in TREM2 have been associated with increased risk of AD.
“Mutations in TREM2 have been associated with increased risk of AD [5, 18].”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [5]
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 [15]
TREM2 R47H mutations impair ApoE binding and increase the risk of human AD.
“TREM2 R47H mutations impair ApoE binding88 and increase the risk of human AD,93”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [93]
Several variants in TREM2 have been linked to increased LOAD risk.
“Several variants in TREM2 have been linked to increased LOAD risk [1, 6].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [6]
The last decade has seen a plethora of studies linking immune-related genes to AD.
“The last decade has seen a plethora of studies linking immune-relate genes to AD [1, 6]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [6]
TREM2 p.H157Y (rs2234255) has been detected in Caucasians, Chinese, and Japanese.
“For example, TREM2 p.H157Y (rs2234255) has been detected not only in Caucasians [35] but also in Chinese [40] and Japanese [24], and the significance of this variant has been confirmed in the Chinese population (Table 4) [40].”
From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [35]
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 [35]
Rare 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 [39]
In the common variation dataset, defining genes without surrounding genomic sequence produced the most significant excess of enriched pathways.
“Genes were defined without surrounding genomic sequence, as this yielded the most significant excess of enriched pathways in the common variation dataset11.”
From Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease (2017) · cites this paper as [11]
The Methods sections describe TREM2 variant analysis and a meta-analysis of genomewide association studies, but do not compare gene definitions or report pathway enrichment. Searches for the claimed excess of enriched pathways and for genes defined without surrounding genomic sequence found no passage addressing either point. Page numbers were not available in our copy. (LLM, conf=0.75)
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 [12]
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 [8]
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 [8]
When not considering fetal astrocytes, mature astrocytes (21%) and microglial cells (20.3%) became the highest expressed cell types in the genome-wide set of genes, with 5.3% of the 400 genes showing high microglial expression.
“When not considering fetal astrocytes, mature astrocytes (21%), and microglial cells (20.3%), the resident macrophage cells of the brain thought to play a key role in the pathologic immune response in LOAD8,14,60, became the highest expressed cell types in the genome-wide set of genes, with 5.3% of the 400 genes showing high microglial expression”
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 [8]
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 [107]
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 [107]
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 [120]
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 Guerreiro et al., 2013
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 Guerreiro et al., 2013
TREM2 variants confer a 2 to 4-fold increased risk for AD.
“Notably, variants of TREM2, an immunoglobulin-like cell-surface receptor primarily expressed on microglia in the brain, were recently found to confer a 2 to 4-fold increased risk for AD [83].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [83]
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 [163]
Many risk genes for Alzheimer's disease are exclusively or highly expressed in myeloid cells.
“Many risk genes for the development of Alzheimer’s disease (AD) are exclusively or highly expressed in myeloid cells.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [5]
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 [127]
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 Guerreiro et al., 2013
TREM2 expression is strongly increased by amyloid deposition in APP transgenic mice.
“and identified that its expression was strongly increased by amyloid deposition in APP transgenic mice (Guerreiro et al., 2013; Matarin et al., 2015; Cheng-Hathaway et al., 2018; Song et al., 2018).”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Guerreiro 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 Guerreiro 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 [24]
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 [132]
Mutation in TREM2 is associated with a three-fold higher risk to develop Alzheimer's disease.
“The mutation in TREM2, has been associated with a three-fold higher risk to develop AD [122].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [122]
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 [56]
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 [56]
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 [2]
This might be one of the major mechanisms underlying various neurodegenerative diseases with advanced age by suppression of WT TREM2 in many sporadic cases, considering that TREM2 variants associated with loss-of-function are extremely rare in frequency in humans.
“This might be one of the major mechanisms underlying various neurodegenerative diseases with advanced age by suppression of WT TREM2 in many sporadic cases, considering that TREM2 variants associated with loss-of-function are extremely rare in frequency in humans (2).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [2]
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 [32]
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The Sequence Alignment/Map format and SAMtools
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Microglia: Dynamic Mediators of Synapse Development and Plasticity
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Self-citationMicroglial dysfunction in brain aging and Alzheimer's disease
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Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
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New insights on the role of microglia in synaptic pruning in health and disease
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Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight
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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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Self-citation
- Authors
- Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., Hazrati, L., Collinge, J., Pocock, J., Lashley, T., Williams, J., Lambert, J.-C., Amouyel, P., Goate, A., Rademakers, R., Morgan, K., Powell, J., St. George-Hyslop, P., Singleton, A., & Hardy, J.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2013-01-10
- Volume
- 368
- Issue
- 2
- Pages
- 117-127
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3631573
- OpenAlex
- W2124490243
- Cited by
- 3,020
- References
- 33
- Citations by year
- 2026: 165 · 2025: 204 · 2024: 238 · 2023: 245 · 2022: 265 · 2021: 250 · 2020: 269 · 2019: 234 · 2018: 251 · 2017: 203 · 2016: 194 · 2015: 196 · 2014: 160 · 2013: 137 · 2012: 6
- FWCI
- 106.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship@McGill (McGill) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Funders
- U.S. Department of Health and Human Services
- University of Dundee
- Wellcome Trust (WT089698, 089703, 081864, 089698, 095317)
- Alzheimer Society
- National Institute for Health and Care Research (NF-SI-0512-10033)
- University College London
- Fondation pour la Recherche sur Alzheimer
- National Institutes of Health (5p30ns069329-02)
- Canadian Institutes of Health Research
- Medical Research Council (MC_G1000735, MR/K013041/1)
- National Institute on Aging (R01AG042611, R01AG018023, U01AG006786, R01-AG18023, R01AG041797, P50AG008702, Z01AG000950, P50AG005681, U24AG056270, U24AG021886, P50AG016574)
- National Institute of Neurological Disorders and Stroke (P30-NS069329, 5P30 NS069329-02)
- 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 › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- TREM2, Alzheimer's disease, loss-of-function mutations, rare variants, genetic risk, mouse models of Alzheimer's disease, early-onset dementia, myeloid cells
- MeSH terms
- Aged, Alzheimer Disease, Animals, Brain, Genotype, Heterozygote, Humans, Membrane Glycoproteins, Mice, Inbred A, Mutation, Receptors, Immunologic, Risk Factors, RNA, Messenger, Genetic Variation, Sequence Analysis, DNA, Mice, Genome-Wide Association Study, Exome, Genotyping Techniques
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