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The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders
Open accessAbstract
Alzheimer's disease is a genetically complex disorder; rare variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene have been shown to as much as triple an individual's risk of developing Alzheimer's disease. TREM2 is a transmembrane receptor expressed in cells of the myeloid lineage, and its association with Alzheimer's disease supports the involvement of immune and inflammatory pathways in the cause of the disease, rather than as a consequence of the disease. TREM2 variants associated with Alzheimer's disease induce partial loss of function of the TREM2 protein and alter the behaviour of microglial cells, including their response to amyloid plaques. TREM2 variants have also been shown to cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy and frontotemporal dementia. Although the low frequency of TREM2 variants makes it difficult to establish robust genotype-phenotype correlations, such studies are essential to enable a comprehensive understanding of the role of TREM2 in different neurological diseases, with the ultimate goal of developing novel therapeutic approaches.
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“Whole-genome analysis led to the identification of relatively rare mutations in TREM2 gene that are associated with a high AD risk.187”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [187]
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“Blocking the activity of this pathway in mouse models of AD has shown to protect synapses by preventing synaptic degeneration and memory impairment [31,32].”
BackgroundFirdaus, Z., & Li, X. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25042320 · Cited by 46
“Within each population, these variants cause a roughly 2–4-fold increase in the risk of developing LOAD [148].”
BackgroundRoles of TREM2 in the Pathological Mechanism and the Therapeutic Strategies of Alzheimer's Disease
Lin, M., Yu, J., Zhang, W., Lao, F., & Huang, H. (2024) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2024.164 · Cited by 46
Therapeutic potential of ADAM10 modulation in Alzheimer’s disease: a review of the current evidence
Khezri, M. R., Mohebalizadeh, M., & Ghasemnejad‐Berenji, M. (2023) · Cell Communication and Signaling · doi:10.1186/s12964-023-01072-w · Cited by 42
“Some studies have also shown that alleles in the TREM2 gene are 3–5 times more likely to develop AD [12].”
BackgroundČuperlović‐Culf, M., & Badhwar, A. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2020.1674808 · Cited by 40
“variations in microglia’s immune receptor genes increase the risk of late-onset AD [21].”
BackgroundAbrogation of type-I interferon signalling alters the microglial response to Aβ1–42
Moore, Z., Mobilio, F., Walker, F. R., Taylor, J. M., & Crack, P. J. (2020) · Scientific Reports · doi:10.1038/s41598-020-59917-0 · Cited by 38
Emerging genetic complexity and rare genetic variants in neurodegenerative brain diseases
Perrone, F., Cacace, R., van der Zee, J., & Broeckhoven, C. V. (2021) · Genome Medicine · doi:10.1186/s13073-021-00878-y · Cited by 38
“Rare heterozygous TREM2 mutations that increase the risk for developing disease have been described in AD, FTD, ALS, and PD [51], though their role in disease pathogenesis needs further follow-up.”
BackgroundInfluentialWijesinghe, P., Whitmore, C. A., Campbell, M., Li, C. H., Tsuyuki, M., To, E. C., Haynes, J. R., Pham, W. N., & Matsubara, J. A. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1107436 · Cited by 37
“Moreover, dysfunction of innate immunity, mainly involving microglia and peripheral myeloid cells, has been suggested as a critical reason in the development of AD (Bradshaw et al., 2013; Vasquez et al., 2013; Carmona et al., 2018).”
BackgroundTargeting epigenetics: A novel promise for Alzheimer’s disease treatment
Jeremic, D., Jiménez‐Díaz, L., & Navarro‐López, J. D. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102003 · Cited by 36
Zhao, L., Yu, S., Li, L., Zhou, C., Wang, L., Tang, S., Gu, N., Zhang, Z., Huang, Z., Chen, H., et al. (2024) · Clinical and Translational Medicine · doi:10.1002/ctm2.1665 · Cited by 38
The vexing complexity of the amyloidogenic pathway
Castro, M., Hadziselimovic, A., & Sanders, C. R. (2019) · Protein Science · doi:10.1002/pro.3606 · Cited by 40
Schwartz, M., Ramos, J. M. P., & Ben-Yehuda, H. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1900844 · Cited by 31
Tucker, A. E., Pauneto, C. D. M. A., Barnett, A., & Coleman, L. G. (2022) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.886634 · Cited by 33
Alzheimer's disease – Where do we go from here?
Борисович, Б. И. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.08.075 · Cited by 34
Edwin, T. H., Henjum, K., Nilsson, L. N. G., Watne, L. O., Persson, K., Eldholm, R. S., Saltvedt, I. T., Halaas, N. B., Selbæk, G., Engedal, K., et al. (2020) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12128 · Cited by 35
Protein and Gene Delivery Systems for Neurodegenerative Disorders: Where Do We Stand Today?
Siafaka, P. I., Okur, M. E., Dilsiz, P., Çağlar, E. Ş., Özgenç, E., Gündoğdu, E., Köprülü, R. E. P., Karantas, I. D., & Okur, N. Ü. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14112425 · Cited by 34
“AD seems to deactivate APP, presenilin-1 (PSEN1), and presenilin-2, presenting a complex genetic architecture with rare, highly penetrating mutations in the genes coding for (PSEN2) [61].”
BackgroundRusty Microglia: Trainers of Innate Immunity in Alzheimer's Disease
Sfera, A., Gradini, R., Cummings, M., Diaz, E. L., Price, A. I., & Osorio, C. P. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.01062 · Cited by 32
Hernández, E. R., Sánchez-Maldonado, C., Chávez, M. Á. M., Hernández-Zimbrón, L. F., Patricio-Martínez, A., Zenteno, E., & Limón, I. D. (2020) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2020.1750955 · Cited by 33
Osteoporosis and Dementia: Establishing a Link
Lary, C. W., Rosen, C. J., & Kiel, D. P. (2021) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4431 · Cited by 31
“This gene is also known to regulate osteoclastogenesis((22)) and is important in AD, especially in the microglia.((23,24)) The gene FNDC5, or Irisin, which results through cleavage of the protein precursor, has been shown to have exercise-mediated effects on bone((25-27)) and to have important effects in AD.”
BackgroundWang, Z., Zhang, Q., Lin, J.-R., Jabalameli, M. R., Mitra, J., Nguyen, N., & Zhang, Z. D. (2021) · Scientific Reports · doi:10.1038/s41598-021-99352-3 · Cited by 29
Thyroid dysfunction and Alzheimer's disease, a vicious circle
Li, Z., & Liu, J. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1354372 · Cited by 29
Mani, S., Wasnik, S., Shandilya, C., Srivastava, V., Khan, S., & Singh, K. K. (2025) · Frontiers in Aging · doi:10.3389/fragi.2025.1615764 · Cited by 33
Qin, Q., Wan, H., Wang, D., Li, J., Qu, Y., Zhao, J., Li, J., & Xue, Z. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.892493 · Cited by 29
“Previous studies had confirmed that TREM2 mutations increased the risk of Alzheimer’s disease (AD) (Carmona et al., 2018), whereas the association of TREM2 mutations with PD remains controversial (Benitez and Cruchaga, 2013; Rayaprolu et al.”
ResultNeuroinflammatory Pathways in the ALS-FTD Continuum: A Focus on Genetic Variants
Marchi, F. D., Tondo, G., Corrado, L., Menegon, F., Aprile, D., Anselmi, M., D’Alfonso, S., Comi, C., & Mazzini, L. (2023) · Genes · doi:10.3390/genes14081658 · Cited by 31
“However, a large amount of data suggests the involvement of TREM2 in AD and other neurodegenerative dementia [124].”
BackgroundPsilocybin for the treatment of Alzheimer’s disease
Zheng, S., Ma, R., Yang, Y., & Li, G. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1420601 · Cited by 27
Zhou, W., He, J., Shen, G., Liu, Y., Zhao, P., & Li, J. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-07002-z · Cited by 28
Review: Molecular pathology of frontotemporal lobar degenerations
Borroni, B., Alberici, A., & Buratti, E. (2018) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12534 · Cited by 26
The Potential Roles of Redox Enzymes in Alzheimer’s Disease: Focus on Thioredoxin
Jia, J., Zeng, X., Xu, G., & Wang, Z. (2021) · ASN NEURO · doi:10.1177/1759091421994351 · Cited by 26
“Triggering receptor expressed in myeloid cells 2 (TREM2) is a microglial cell surface receptor central to proliferation, survival, and phagocytosis of microglia (Carmona et al., 2018).”
BackgroundNeurodegenerative phagocytes mediate synaptic stripping in Neuro-HIV
Liberto, G. D., Égervári, K., Kreutzfeldt, M., Schürch, C. M., Hewer, E., Wagner, I., Pasquier, R. D., & Merkler, D. (2022) · Brain · doi:10.1093/brain/awac102 · Cited by 28
“microglia, more neuritic dystrophy and increased risk of late-onset Alzheimer’s disease, suggesting a protective role of this receptor in disease development.(75) In mice, TREM2-deficient microglia do not exhibit the typical increase in expression of HLA markers or DAM markers and are locked into amore homeostatic phe…”
Lu, Y., Huang, X., Liang, W., Li, Y., Xing, M., Pan, W., Zhang, Y., Wang, Z., & Song, W. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104688 · Cited by 26
“All of these functions of microglia are compromised in AD (4).”
BackgroundDoes the CD33 rs3865444 Polymorphism Confer Susceptibility to Alzheimer’s Disease?
Siokas, V., Aslanidou, P., Aloizou, A., Peristeri, E., Stamati, P., Liampas, I., Arseniou, S., Drakoulis, N., Aschner, M., Tsatsakis, A. M., et al. (2020) · Journal of Molecular Neuroscience · doi:10.1007/s12031-020-01507-w · Cited by 49
“The ε4 allele of Apolipoprotein E (APOE) is a genetic risk factor consistently implicated in AD (Carmona et al. 2018; Panegyres and Chen 2013), although it can only partially account for ADmanifestation (Jiang et al.”
BackgroundQuinoline-Pyrazole Scaffold as a Novel Ligand of Galectin-3 and Suppressor of TREM2 Signaling
Gabr, M. T., Rehman, A. U., & Chen, H. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00330 · Cited by 23
Chib, S., Dutta, B. J., Chalotra, R., Abubakar, M., Kumar, P., Singh, T. G., & Singh, R. (2024) · Phytotherapy Research · doi:10.1002/ptr.8406 · Cited by 24
“…Binding Clathrin Assembly Brotein (PICALM), (Harold et al. 2009; Lambert et al. 2009), Trigging Receptor Expressed on Myeloid Cells-2 (TREM2) (Carmona et al. 2018), Sortilin-related Receptor gene 1 (SORL1) (Yin, Yu, and Tan 2015), Phospholipase D3 PLD3 (Nackenoff et al. 2021), Presenilin 1,2…”
Huang, Y., & Fang, W. (2025) · npj Precision Oncology · doi:10.1038/s41698-025-01152-9 · Cited by 30
Oblak, A. L., Kotredes, K. P., Pandey, R. S., Reagan, A. M., Ingraham, C., Perkins, B., Lloyd, C., Baker, D., Lin, P. B., Soni, D. M., et al. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.886575 · Cited by 23
“Although the precise effects of the M28L variant have not yet been elucidated, like TREM2, PLCG2 is expressed by microglia and plays a role in amyloid clearance (Carmona et al., 2018).”
BackgroundWang, R., Zhan, Y., Zhu, W., Yang, Q., & Pei, J. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1407980 · Cited by 25
“Genetic variations significantly affect TREM2’s structure and function, and a GWAS has identified 46 TREM2 variants linked with AD that increase the risk of late-onset AD (Carmona et al., 2018).”
BackgroundThe double-edged role and therapeutic potential of TREM2 in atherosclerosis
Zhu, B., Liu, Y., & Peng, D. (2024) · Biomarker Research · doi:10.1186/s40364-024-00675-w · Cited by 28
TREM2 in Neurodegenerative Disorders: Mutation Spectrum, Pathophysiology, and Therapeutic Targeting
Yang, H.-W., Kim, D., Yang, Y., Bagyinszky, E., & An, S. S. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157057 · Cited by 26
“These selective binding differences may help to explain how Arg62His could affect microglial activity and offer valuable insights into AD pathogenesis [17,107,137].”
Metadata
- Authors
- Carmona, S., Zahs, K., Wu, E., Dakin, K., Bras, J., & Guerreiro, R.
- Affiliations
- UK Dementia Research Institute (GB)
- Alzforum (US)
- Corresponding author
- Guerreiro, Rita
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 17
- Issue
- 8
- Pages
- 721-730
- ISSN
- 1474-4422 (ISSN-L)
- OpenAlex
- W2884070953
- Cited by
- 244
- References
- 107
- Citations by year
- 2026: 13 · 2025: 28 · 2024: 42 · 2023: 38 · 2022: 30 · 2021: 32 · 2020: 28 · 2019: 28 · 2018: 4
- FWCI
- 2.18
- Type
- journal article
- Language
- en
- Open access
- green
- discovery.ucl.ac.uk
- Licence
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion, other-oa)
- Funders
- Alzheimer's Society
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, Alzheimer's disease, neurodegenerative diseases, myeloid cells, microglia, amyloid plaques, neuroinflammation, genetic risk variants, loss-of-function mutations, frontotemporal dementia, genotype-phenotype correlation, therapeutic target
- MeSH terms
- Alzheimer Disease, Humans, Membrane Glycoproteins, Receptors, Immunologic, Neurodegenerative Diseases, Genetic Predisposition to Disease
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