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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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“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]
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“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]
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“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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“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].”
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“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).”
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“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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“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).”
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Zhao, J., Ren, T., Li, X., Guo, T.-L., Liu, C., & Wang, X. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.831977 · Cited by 22
“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 22
“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].”
Marín-Castañeda, L. A., González-Garibay, G., Garcia-Quintana, I., Aispuro, G. P., & Rubio, C. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1494356 · Cited by 16
Microglial Modulation in Alzheimer’s Disease: Central Players in Neuroinflammation and Pathogenesis
Hussain, M. S., Khan, Y., Fatima, R., Maqbool, M., Ramalingam, P. S., Khan, M. G., & Bisht, A. S. (2025) · Current Alzheimer Research · doi:10.2174/0115672050364292250113063513 · Cited by 15
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Bustos, C., Ortega-Rojas, J., Mahecha, M. F., Arboleda, G., Vásquez, R., Pardo, R., & Arboleda, H. (2018) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0000000000000275 · Cited by 10
Multi-scale modeling for systematically understanding the key roles of microglia in AD development
Ji, Z., Liu, C., Zhao, W., Soto, C. A., & Zhou, X. (2021) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2021.104374 · Cited by 10
Almalki, W. H., & Almujri, S. S. (2024) · Pathology - Research and Practice · doi:10.1016/j.prp.2024.155614 · Cited by 9
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Zhao, K., Wu, Y., Zhao, D., Zhang, H., Lin, J., & Wang, Y. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1125281 · Cited by 10
“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).”
BackgroundBandow, K., Smith, A., & Garlick, J. A. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.10.048 · Cited by 8
Potential Molecular Mechanisms of Alzheimer’s Disease from Genetic Studies
Nwadiugwu, M. C., Shen, H., & Deng, H. (2023) · Biology · doi:10.3390/biology12040602 · Cited by 8
“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.”
Zhang, Y., Guo, X., Zhao, J., Gao, X., Zhang, L., Huang, T., Wang, Y., Niu, Q. L., & Zhang, Q. (2024) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2024.117107 · Cited by 8
Liu, J., Zhang, Z., Zhou, M., Ling, S., Zhou, X., Yuan, B., Zhao, X., Qi, M., Han, Y., Qin, F., et al. (2024) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2902050 · Cited by 6
“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].”
BackgroundLi, H., Xie, Z., Tian, Y., Zhou, R., Yang, Y., Lin, B., Chen, S., Wu, J., Deng, Z., Li, J., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03318-0 · Cited by 7
Rikos, D., Siokas, V., Mentis, A. A., Aloizou, A., Liampas, I., Tsouris, Z., Peristeri, E., Stamati, P., Hadjigeorgiou, G. M., & Dardiotis, E. (2022) · International Journal of Neuroscience · doi:10.1080/00207454.2022.2150844 · Cited by 15
TREM2 coding variants in Slovak Alzheimer's disease patients
Ďurmanová, V., Javor, J., Párnická, Z., Minárik, G., Ocenasova, A., Vašečková, B., Kiralyova, I., Šutovský, S., Petrovič, R., & Shawkatová, I. (2022) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2104105 · Cited by 5
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Bibliometric Analysis of TREM2 (2001-2022): Trends, Hotspots and Prospects in Human Disease
Qian, M., Zhong, J., Lu, Z., Zhang, W., Weng, M., Zhang, K., & Jin, Y. (2024) · International Journal of Medical Sciences · doi:10.7150/ijms.96851 · Cited by 4
Emerging Microglial Therapies and Targets in Clinical Trial
Yan, L., & Crotti, A. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-55529-9_35 · Cited by 2
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Pottorf, T. S., Lane, E. L., & Álvarez, F. J. (2025) · Cells · doi:10.3390/cells14191520 · Cited by 1
Tang, H.-L., Min, Y., & Long, Y. (2026) · PLoS ONE · doi:10.1371/journal.pone.0344387 · Cited by 1
“…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
Ris, L. (2024) · Springer eBooks · doi:10.1007/978-3-031-24297-7_9-1 · Cited by 1
Protective Effects of Cannabis in Neuroinflammation-Mediated Alzheimer's Disease
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“Many lines of evidence strongly implicate microglial inflammation in the pathophysiology of AD [31, 33, 42, 45, 80-83].”
BackgroundLi, R., Zhang, J., Wang, Q., Cheng, M., & Lin, B. (2022) · Figshare · doi:10.6084/m9.figshare.21340397
Origin, Diversity, and Roles of Microglia
Ris, L. (2024) · Springer eBooks · doi:10.1007/978-3-031-60006-7_9
Narita, K., Yoshioka, Y., Abdali, S. S., Ohgidani, M., Komaki, S., Shimizu, A., & Saino, T. (2025) · Research Square · doi:10.21203/rs.3.rs-7569057/v1
Li, R., Zhang, J., Wang, Q., Cheng, M., & Lin, B. (2022) · Figshare · doi:10.6084/m9.figshare.21340406
Li, R., Zhang, J., Wang, Q., Cheng, M., & Lin, B. (2022) · Figshare · doi:10.6084/m9.figshare.21340415
Li, R., Zhang, J., Wang, Q., Cheng, M., & Lin, B. (2022) · Figshare · doi:10.6084/m9.figshare.21340400
Li, R., Zhang, J., Wang, Q., Cheng, M., & Lin, B. (2022) · Figshare · doi:10.6084/m9.figshare.21340421
Li, R., Zhang, J., Wang, Q., Cheng, M., & Lin, B. (2022) · Figshare · doi:10.6084/m9.figshare.21340412
Li, R., Zhang, J., Wang, Q., Cheng, M., & Lin, B. (2022) · Figshare · doi:10.6084/m9.figshare.21340403
Li, R., Zhang, J., Wang, Q., Cheng, M., & Lin, B. (2022) · Figshare · doi:10.6084/m9.figshare.21340427
Li, R., Zhang, J., Wang, Q., Cheng, M., & Lin, B. (2022) · Figshare · doi:10.6084/m9.figshare.21340424
Li, R., Zhang, J., Wang, Q., Cheng, M., & Lin, B. (2022) · Figshare · doi:10.6084/m9.figshare.21340418
Interferon-γ-activated adult human astrocytes induce pyroptosis in neuroblastoma cells
Matsuda, T., Omiya, Y., Shimizu, T., Sato, H., Hishiyama, M., Tang, M., Kinoshita, M., Hara, H., & Hashioka, S. (2026) · Brain Mechanisms · doi:10.1016/j.bramec.2026.202542
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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”.”
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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