The triggering receptor expressed on myeloid cells 2 ( TREM2 ) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia
Open accessAbstract
Introduction: The objective of this study was to elucidate the relationship between the triggering receptor expressed on myeloid cells 2 ( TREM2 ) risk variant, neuropathological lesions, alterations in gene and protein expression, and the severity of neuroinflammation. Methods: The genetic association study of the R47 H TREM2 variant with Alzheimer's disease (AD), neuropathology, and changes in TREM2 and TYRO protein tyrosine kinase‐binding protein ( TYROBP) gene and protein expression, and neuroinflammatory markers. Results: The TREM2 variant is associated with: (i) AD (odds ratio: 4.76; P = .014); (ii) increased density of amyloid plaques and neurofibrillary tangles in multiple brain regions; (iii) increased TREM2 ( P = .041) and TYROBP ( P = .006) gene expression; (iv) decreased TREM2 protein levels ( P = .016); and (v) upregulation of proinflammatory cytokines (regulated on activation, normal T cell expressed and secreted [RANTES] and interferon [IFN] gamma) ( P = .003) and nominal downregulation of protective markers (α2‐macroglobulin, interleukin 4 or IL‐4, and ApoA1) ( P = .018). Discussion: These findings link the TREM2 missense mutation with specific molecular abnormalities and increases in neuropathological lesions in the human brain.
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Roussos et al. reported higher TREM2 gene expression in Alzheimer's disease R47H carriers relative to controls and no difference in TREM2 between Alzheimer's disease noncarriers and control.
“They also reported higher TREM2 gene expression in AD R47H carriers relative to controls and no difference in TREM2 between AD noncarriers and control.”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [107]
Results §3.4 reports significantly higher TREM2 gene expression in AD R47H carriers than in controls. It does not explicitly report no difference between AD noncarriers and controls; the Discussion (§4) instead describes noncarriers as showing intermediate changes in expression. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRoussos et al. protein measurements indicated decreased TREM2 in Alzheimer's disease R47H carriers relative to controls with no difference between Alzheimer's disease noncarriers and control.
“Their protein measurements, however, indicated decreased TREM2 in AD R47H carriers relative to controls with no difference between AD noncarriers and control.”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [107]
Results §3.5 reports higher TREM2 protein in controls than in AD R47H carriers (P = 0.014), supporting the first comparison. It does not report a TREM2 comparison between AD noncarriers and controls, so the claimed absence of a difference is not established by our copy. Page numbers were not available. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSeveral other TREM2 variants (R62H, T66M, H157Y, D87N) increase the risk of AD.
“Several other TREM2 variants that affect the expression of TREM2 also increased the risk of AD, including R62H, T66M, H157Y, and D87N.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [165]
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“In carriers of TREM2 mutations, the inflammation response is much enhanced, and pro-inflammatory cytokines are increased (Roussos et al., 2015).”
BackgroundPrecision pharmacology for Alzheimer’s disease
Hampel, H. J., Vergallo, A., Aguilar, L. F., Benda, N., Broich, K., Cuello, A. C., Cummings, J. L., Dubois, B., Federoff, H. J., Fiandaca, M. S., et al. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.02.014 · Cited by 112 · see citing works
TREM2 brain transcript-specific studies in AD and TREM2 mutation carriers
Del‐Aguila, J. L., Benítez, B. A., Li, Z., Dube, U., Mihindukulasuriya, K. A., Budde, J., Farias, F., Fernández, M. V., Ibáñez, L., Jiang, S., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0319-3 · Cited by 103 · see citing works
“R47H was validated in neuropathological-confirmed cases [25] and was shown to increase the risk for late onset AD to a similar extent as the ApoE ɛ4 allele [15, 18].”
Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings
de Oliveira, J., Kucharska, E., Garcez, M. L., Rodrigues, M. S., Quevedo, J., Moreno‐González, I., & Budni, J. (2021) · Cells · doi:10.3390/cells10102581 · Cited by 105 · see citing works
“This polymorphism has been validated in neuropathology-confirmed cases and has been shown to increase the risk of sporadic AD as significantly as the ApoE ε4 allele [106].”
Apolipoprotein E4 and meningeal lymphatics in Alzheimer disease: a conceptual framework
Mentis, A. A., Dardiotis, E., & Chrousos, G. P. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0731-7 · Cited by 82 · see citing works
“Sources: a [7]; b [220]; c [234]; d [235]; e [62]; f [21]; g [8]; h [236]; i [237, 238]; j [239]; k [240]; l [241]; m [242]; n [243]; o [244]; p [245]; q [246]; r [246]; s [247]; t [248]; u [249]; v [250], [251, 252]; w [253]; x [254]; y [255, 256].”
Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson’s Disease Susceptibility
Liu, G., Liu, Y., Jiang, Q., Jiang, Y., Feng, R., Zhang, L., Chen, Z., Li, K., & Liu, J. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9416-7 · Cited by 83 · see citing works
Oxidative stress–mediated neuroinflammation in Alzheimer’s disease
Firdous, S. M., Khan, S. A., & Maity, A. (2024) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-024-03188-3 · Cited by 85 · see citing works
“Recent research underscores the potential impact of myeloid cell-expressed triggering receptor 2 (TREM2) on AD etiology, neurodegeneration, and neuroin-flammation (Roussos et al. 2015).”
Early Life Stress and Epigenetics in Late-onset Alzheimer’s Dementia: A Systematic Review
Lemche, E. (2018) · Current Genomics · doi:10.2174/1389202919666171229145156 · Cited by 82 · see citing works
“1 IL4 Interleukin 4: adaptive immunity, chronic inflammation, mediating neurodegeneration, regeneration cascade through effector STAT6, interacting with TREM2 and TYROBP [651, 718] 7p15.”
InfluentialGu, X., CAI, Z., Cai, M., Liu, K., Liu, D., ZHANG, Q., Tan, J. H., & Ma, Q. (2016) · Molecular Medicine Reports · doi:10.3892/mmr.2016.4805 · Cited by 81 · see citing works
“Activated microglia and astrocytes express a large quantity of inflammatory cytokines, such as TNF‑ α , IL-1 β and IL-6, and specific receptors on the cell surface are involved in inflammation and death of neighboring cells in the brain (27).”
Glia-Driven Neuroinflammation and Systemic Inflammation in Alzheimer’s Disease
Hashioka, S., Wu, Z., & Klegeris, A. (2021) · Current Neuropharmacology · doi:10.2174/1570159x18666201111104509 · Cited by 78 · see citing works
“A post-mortem genetic association study has shown upregulation of IFN-γ in the brains of AD patients who carry the R47H TREM2 variant [123].”
BackgroundTREM2 regulates innate immunity in Alzheimer’s disease
Li, J.-T., & Zhang, Y. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1148-y · Cited by 76 · see citing works
“[27], T66M [26], R62H [28], R47H [27], and Q33X [29] (Fig.”
Koronyo‐Hamaoui, M., Sheyn, J., Hayden, E. Y., Li, S., Fuchs, D.-T. S., Regis, G. C., Lopes, D. H. J., Black, K. L., Bernstein, K. E., Teplow, D. B., et al. (2019) · Brain · doi:10.1093/brain/awz364 · Cited by 70 · see citing works
“, 2016; Johnson and Stevens, 2018), while insufficiently clearing misfolded amyloid-b (Morgan et al., 2005; Simard et al., 2006; El Khoury et al., 2007; Hickman et al., 2008; Koronyo-Hamaoui et al., 2009; Yamanaka et al., 2012; Frenkel et al., 2013; Roussos et al., 2015).”
BackgroundTREM2 Variants and Neurodegenerative Diseases: A Systematic Review and Meta-Analysis
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“TREM2 variants in AD are also associated with enhanced inflammatory responses (upregulation of proinflammatory cytokines) [136].”
BackgroundHigh TREM2 expression correlates with poor prognosis in gastric cancer
Zhang, X., Wang, W. T., Li, P., Wang, X., & Ni, K. (2017) · Human Pathology · doi:10.1016/j.humpath.2017.10.026 · Cited by 61 · see citing works
More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer's disease risk
Rosenthal, S. L., Bamne, M. N., Wang, X., Berman, S., Snitz, B. E., Klunk, W. E., Sweet, R. A., Demirci, F. Y., López, O. L., & Kamboh, M. I. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.04.012 · Cited by 53 · see citing works
“…with LOAD Cases Controls Odds Ratio (95% CI) P Publication 474 608 7.87 (1.75-35.34) 0.007 Finelli et al, 2015 265 225 4.76 (1.37-16.54) 0.014 Roussos et al, 2014 3220 3112 1.67 (0.95-2.92) 0.034 Hooli et al, 2014a 917 199 4.97 (1.18-20.80) 0.004 Hooli et al, 2014, NIMHb 860 1036 3.03…”
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Neuroprotection through G-CSF: recent advances and future viewpoints
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Prospects for strain-specific immunotherapy in Alzheimer’s disease and tauopathies
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TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway
Li, R., Zhang, J., Wang, Q., Cheng, M., & Lin, B. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02619-3 · Cited by 39 · see citing works
Li, R., Wang, X., & He, P. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.9778 · Cited by 39 · see citing works
Reduced TREM2 activation in microglia of patients with Alzheimer's disease
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TREM2 variants and risk of Alzheimer’s disease: a meta-analysis
Lu, Y., Liu, W., & Wang, X. (2015) · Neurological Sciences · doi:10.1007/s10072-015-2274-2 · Cited by 37 · see citing works
“reported that TREM2 R47H mutation was associated with increased density of SPs and NFTs in multiple brain regions, as well as upregulation of proinflammatory cytokines [34].”
BackgroundSingle-cell RNA sequencing in atherosclerosis: Mechanism and precision medicine
Li, Q., Wang, M., Zhang, S., Jin, M., Chen, R., Luo, Y., & Sun, X. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.977490 · Cited by 29 · see citing works
“TREM2 is a member of the immunoglobulin superfamily and forms complex with TYRO protein tyrosine kinase-binding protein at cell surface which regulates the activation of macrophages, dendritic cells, osteoclasts and microglial cells (Roussos et al., 2015; Zhang et al., 2018).”
BackgroundTREM2 in Alzheimer's disease: Structure, function, therapeutic prospects, and activation challenges
Zgórzyńska, E. (2024) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2024.103917 · Cited by 28 · see citing works
Roles of TREM2 in Alzheimer’s disease
Qi, X., Zhu, K., Ke, W., Wang, J., Mao, S., & Chen, G. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00515-3 · Cited by 36 · see citing works
“Increased TREM2 expression effectively suppresses neuroinflammation, whereas TREM2 dysfunction amplifies the inflammatory response [94, 95].”
TREMs in Alzheimer's disease: Genetic and clinical investigations
Cheng, J. R., Guo, X., Zhang, T., Zhong, L., Bu, G., & Chen, X. (2016) · Clinica Chimica Acta · doi:10.1016/j.cca.2016.10.022 · Cited by 29 · see citing works
TREM2 risk variants are associated with atypical Alzheimer’s disease
Kim, B., Suh, E. R., Nguyen, A. T., Prokop, S., Mikytuck, B., Olatunji, O. A., Robinson, J. L., Grossman, M., Phillips, J. S., Irwin, D. J., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02495-4 · Cited by 29 · see citing works
“Neuropathologic studies of TREM2 variant cases with ADNC have described increased tau and amyloid-β (Aβ) burden in multiple brain regions [41, 45], a relative loss of amyloid-associated microglia [35, 41], larger amyloid plaque size [22], and increased severity of α-synucleinopathy [24].”
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Molina‐Martínez, P., Corpas, R., García-Lara, E., Cosín‐Tomás, M., Cristòfol, R. M., Kaliman, P., Solà, C., Molinuevo, J. L., Sánchez‐Valle, R., Antonell, A., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.622360 · Cited by 23 · see citing works
“However, previous authors have also shown a trend to increase the overall TREM2 expression levels in sporadic AD cases in comparison to controls (Roussos et al., 2015; Del-Aguila et al., 2019).”
BackgroundResultZhang, X., Chen, X., Zhang, L., Sun, Y., Liang, Y., Li, H., & Zhang, Y. (2023) · Neurochemistry International · doi:10.1016/j.neuint.2023.105639 · Cited by 23 · see citing works
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“Moreover, recent studies have found that TREM2 can increase AD risk by about 3-times (Roussos et al., 2015).”
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“…(predicted to cause an R47H substitution) increases susceptibility to AD (Benitez et al., 2013; Giraldo et al., 2013; Guerreiro et al., 2013; Jonsson et al., 2013; Pottier et al., 2013; Cuyvers et al., 2014; Jin et al., 2014; Roussos et al., 2014; Ruiz et al., 2014; Slattery et al., 2014).”
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TREM2 in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential
Li, L., Zheng, X., Ma, H., Zhu, M., Li, X., Sun, X., & Feng, X. (2025) · Cells · doi:10.3390/cells14171387 · Cited by 20 · see citing works
“Furthermore, 46 TREM2 mutations associated with AD have been identified, including R62H (rs143332484), D87N (rs142232675), T96K (rs2234353), L211P (rs2234256), R136Q (rs149622783), and p.H157Y (rs2234255) [55,97–102], all of which increase the risk of AD development [103].”
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Microglial Modulation in Alzheimer’s Disease: Central Players in Neuroinflammation and Pathogenesis
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Multi-scale modeling for systematically understanding the key roles of microglia in AD development
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“TREM2 is also a very important gene and encodes the protein, triggering receptor expressed on myeloid cells 2 (TREM2); it is expressed by microglia, the resident immune cells of the brain, and strongly affects the lifelong risk of AD (Roussos et al., 2015; Ulrich et al., 2017).”
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Potential Molecular Mechanisms of Alzheimer’s Disease from Genetic Studies
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“While these studies showed that TREM2 loss of function variant R47H was linked with increased neurofibrillary tangles and neuritic plaques in AD [32,33], Okuzono et al.”
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“The triggering receptor expressed on myeloid cells 2 (TREM2), which is selectively and highly expressed on microglia, is the main receptor for inducing the anti-inflammatory response [8].”
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TREM2 coding variants in Slovak Alzheimer's disease patients
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“…linking with greater response to microglial phagocytosis [50], and overactivation of the TYROBP–TREM2 pathway in cell and mouse models of Alzheimer’s disease can lead to excessive synaptic pruning and aberrant neural circuit remodeling, thereby impairing learning and memory functions [51,52].”
Origin, Diversity, and Roles of Microglia
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“Many lines of evidence strongly implicate microglial inflammation in the pathophysiology of AD [31, 33, 42, 45, 80-83].”
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Interferon-γ-activated adult human astrocytes induce pyroptosis in neuroblastoma cells
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“In early disease, TREM2-mediated recruitment of microglia is essential for initiating Aβ clearance and limiting plaque toxicity [29, 33], and at this time, TREM2 acts as a “friend”.”
- Authors
- Roussos, P., Katsel, P., Fam, P., Tan, W., Purohit, D. P., & Haroutunian, V.
- Affiliations
- New York/New Jersey VA Health Care Network (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Haroutunian, Vahram
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2014-12-09
- Volume
- 11
- Issue
- 10
- Pages
- 1163-1170
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC4461564
- OpenAlex
- W2102675610
- Cited by
- 103
- References
- 52
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 11 · 2023: 8 · 2022: 18 · 2021: 8 · 2020: 6 · 2019: 9 · 2018: 9 · 2017: 9 · 2016: 7 · 2015: 3
- FWCI
- 3.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P01‐AG02219, P50‐AG05138, MH066392)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TREM2, Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Brain, Female, Humans, Inflammation, Membrane Glycoproteins, Receptors, Immunologic, Risk, Interleukin-4, Gene Expression, Case-Control Studies, Mutation, Missense, Myeloid Cells, Apolipoprotein E4, Genetic Association Studies, Plaque, Amyloid
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