Review Article | Published:

TREM2 — a key player in microglial biology and Alzheimer disease

Nature Reviews Neurologyvolume 14pages667675 (2018) | Download Citation


Alzheimer disease (AD) is a debilitating dementia believed to result from the deposition of extracellular amyloid-β (Aβ)-containing plaques followed by the formation of neurofibrillary tangles. Familial AD typically results from mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 or presenilin 2. Variations in triggering receptor expressed on myeloid cells 2 (TREM2), one of several genes for which expression is restricted to microglia in the brain, have now been shown to increase the risk of developing late-onset AD. Microglia have been shown to respond to Aβ accumulation and neurodegenerative lesions, progressively acquiring a unique transcriptional and functional signature and evolving into disease-associated microglia (DAM). DAM attenuate the progression of neurodegeneration in certain mouse models, but inappropriate DAM activation accelerates neurodegenerative disease in other models. TREM2 is essential for maintaining microglial metabolic fitness during stress events, enabling microglial progression to a fully mature DAM profile and ultimately sustaining the microglial response to Aβ-plaque-induced pathology. Here, we review the current data detailing the role of TREM2 in microglial biology and AD.

Key points

  • During the development of Alzheimer disease (AD)-associated pathology, homeostatic microglia progressively acquire a unique transcriptional and functional signature and evolve into disease-associated microglia (DAM).

  • DAM can contain amyloid-β plaques and protect surrounding neuronal tissue.

  • Rare loss-of-function variants in the gene encoding triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of developing AD in humans.

  • Microglia require TREM2 for full acquisition of a DAM profile.

  • TREM2 is needed to enhance mechanistic target of rapamycin (mTOR) signalling and to boost the metabolic capacity of microglia.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement. 12, 459–509 (2016).

  2. 2.

    Holtzman, D. M., Morris, J. C. & Goate, A. M. Alzheimer’s disease: the challenge of the second century. Sci. Transl Med. 3, 77sr71 (2011).

  3. 3.

    St George-Hyslop, P. H. et al. The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 235, 885–890 (1987).

  4. 4.

    Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760 (1995).

  5. 5.

    Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706 (1991).

  6. 6.

    Levy, E. et al. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248, 1124–1126 (1990).

  7. 7.

    Levy-Lahad, E. et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977 (1995).

  8. 8.

    Rogaev, E. I. et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775–778 (1995).

  9. 9.

    Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).

  10. 10.

    Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).

  11. 11.

    Sims, R. et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1384 (2017).

  12. 12.

    Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet. 43, 429–435 (2011).

  13. 13.

    Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).

  14. 14.

    Strittmatter, W. J. et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977–1981 (1993).

  15. 15.

    Song, W. et al. Alzheimer’s disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement. 13, 381–387 (2017).

  16. 16.

    Benitez, B. A. et al. TREM2 is associated with the risk of Alzheimer’s disease in Spanish population. Neurobiol. Aging 34, 1711 (2013).

  17. 17.

    Ruiz, A. et al. Assessing the role of the TREM2 p. R47H variant as a risk factor for Alzheimer’s disease and frontotemporal dementia. Neurobiol. Aging 35, 444 (2014).

  18. 18.

    Slattery, C. F. et al. R47H TREM2 variant increases risk of typical early-onset Alzheimer’s disease but not of prion or frontotemporal dementia. Alzheimers Dement. 10, 602–608 (2014).

  19. 19.

    Karch, C. M., Cruchaga, C. & Goate, A. M. Alzheimer’s disease genetics: from the bench to the clinic. Neuron 83, 11–26 (2014).

  20. 20.

    Bertram, L. et al. Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am. J. Hum. Genet. 83, 623–632 (2008).

  21. 21.

    Naj, A. C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat. Genet. 43, 436–441 (2011).

  22. 22.

    Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat. Genet. 41, 1088–1093 (2009).

  23. 23.

    Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 41, 1094–1099 (2009).

  24. 24.

    Seshadri, S. et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303, 1832–1840 (2010).

  25. 25.

    Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013).

  26. 26.

    Miyashita, A. et al. SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PLoS ONE 8, e58618 (2013).

  27. 27.

    Nissl, F. in Histologische und histopathologische Arbeiten über die Grosshirnrinde Vol. 1 (eds. Nissl, F., Alzheimer, A.) 315–494 (G. Fischer, Jena, Germany, 1904).

  28. 28.

    Alzheimer, A. in Histologische und histopathologische Arbeiten über die Grosshirnrinde Vol. 3 (eds. Nissl, F., Alzheimer, A.) 401–562 (G. Fischer, Jena, Germany, 1910).

  29. 29.

    Hortega, P. R. El tercer elemento de los centros nerviosos. III. Naturaleza probable de la microglía [Spanish]. Bol. Soc. Esp. Biol. 8, 108–115 (1919).

  30. 30.

    Greter, M. & Merad, M. Regulation of microglia development and homeostasis. Glia 61, 121–127 (2013).

  31. 31.

    Gomez Perdiguero, E., Schulz, C. & Geissmann, F. Development and homeostasis of “resident” myeloid cells: the case of the microglia. Glia 61, 112–120 (2013).

  32. 32.

    Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).

  33. 33.

    Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).

  34. 34.

    Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).

  35. 35.

    Lue, L. F., Kuo, Y. M., Beach, T. & Walker, D. G. Microglia activation and anti-inflammatory regulation in Alzheimer’s disease. Mol. Neurobiol. 41, 115–128 (2010).

  36. 36.

    Neumann, H., Kotter, M. R. & Franklin, R. J. Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132, 288–295 (2009).

  37. 37.

    Butovsky, O. et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosci. 31, 149–160 (2006).

  38. 38.

    Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).

  39. 39.

    Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).

  40. 40.

    Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).

  41. 41.

    Mathys, H. et al. Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 21, 366–380 (2017).

  42. 42.

    Chiu, I. M. et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 4, 385–401 (2013).

  43. 43.

    Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).

  44. 44.

    Vincenti, J. E. et al. Defining the microglia response during the time course of chronic neurodegeneration. J. Virol. 90, 3003–3017 (2015).

  45. 45.

    Alibhai, J. et al. Distribution of misfolded prion protein seeding activity alone does not predict regions of neurodegeneration. PLoS Biol. 14, e1002579 (2016).

  46. 46.

    Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017).

  47. 47.

    Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).

  48. 48.

    Ofengeim, D. et al. RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 114, E8788–E8797 (2017).

  49. 49.

    Deczkowska, A. et al. Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173, 1073–1081 (2018).

  50. 50.

    Kamphuis, W., Kooijman, L., Schetters, S., Orre, M. & Hol, E. M. Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer’s disease. Biochim. Biophys. Acta 1862, 1847–1860 (2016).

  51. 51.

    Bouchon, A., Dietrich, J. & Colonna, M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J. Immunol. 164, 4991–4995 (2000).

  52. 52.

    Cannon, J. P., O’Driscoll, M. & Litman, G. W. Specific lipid recognition is a general feature of CD300 and TREM molecules. Immunogenetics 64, 39–47 (2012).

  53. 53.

    Daws, M. R. et al. Pattern recognition by TREM-2: binding of anionic ligands. J. Immunol. 171, 594–599 (2003).

  54. 54.

    Kawabori, M. et al. Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke. J. Neurosci. 35, 3384–3396 (2015).

  55. 55.

    Xing, J., Titus, A. R. & Humphrey, M. B. The TREM2-DAP12 signaling pathway in Nasu-Hakola disease: a molecular genetics perspective. Res. Rep. Biochem. 5, 89–100 (2015).

  56. 56.

    Peng, Q. et al. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci. Signal. 3, ra38 (2010).

  57. 57.

    Ulland, T. K. et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170, 649–663 (2017).

  58. 58.

    Turnbull, I. R. et al. Cutting edge: TREM-2 attenuates macrophage activation. J. Immunol. 177, 3520–3524 (2006).

  59. 59.

    Piccio, L. et al. Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. Eur. J. Immunol. 37, 1290–1301 (2007).

  60. 60.

    Wunderlich, P. et al. Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase-dependent intramembranous cleavage. J. Biol. Chem. 288, 33027–33036 (2013).

  61. 61.

    Schlepckow, K. et al. An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol. Med. 9, 1356–1365 (2017).

  62. 62.

    Thornton, P. et al. TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant. EMBO Mol. Med. 9, 1366–1378 (2017).

  63. 63.

    Feuerbach, D. et al. ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after histidine 157. Preprint at (2017).

  64. 64.

    Glebov, K., Wunderlich, P., Karaca, I. & Walter, J. Functional involvement of γ-secretase in signaling of the triggering receptor expressed on myeloid cells-2 (TREM2). J. Neuroinflammation 13, 17 (2016).

  65. 65.

    Paloneva, J. et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am. J. Hum. Genet. 71, 656–662 (2002).

  66. 66.

    Klunemann, H. H. et al. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 64, 1502–1507 (2005).

  67. 67.

    Hakola, H. P. Neuropsychiatric and genetic aspects of a new hereditary disease characterized by progressive dementia and lipomembranous polycystic osteodysplasia. Acta Psychiatr. Scand. 232, 1–173 (1972).

  68. 68.

    Cella, M. et al. Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J. Exp. Med. 198, 645–651 (2003).

  69. 69.

    Poliani, P. L. et al. TREM2 sustains microglial expansion during aging and response to demyelination. J. Clin. Invest. 125, 2161–2170 (2015).

  70. 70.

    Otero, K. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin. Nat. Immunol. 10, 734–743 (2009).

  71. 71.

    Zou, W., Reeve, J. L., Liu, Y., Teitelbaum, S. L. & Ross, F. P. DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk. Mol. Cell 31, 422–431 (2008).

  72. 72.

    Guerreiro, R. et al. Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family. Neurobiol. Aging 34, 2890 (2013).

  73. 73.

    Jin, S. C. et al. TREM2 is associated with increased risk for Alzheimer’s disease in African Americans. Mol. Neurodegener. 10, 19 (2015).

  74. 74.

    Jiang, T. et al. A rare coding variant in TREM2 increases risk for Alzheimer’s disease in Han Chinese. Neurobiol. Aging 42, 217 (2016).

  75. 75.

    Huang, M. et al. Lack of genetic association between TREM2 and Alzheimer’s disease in East Asian population: a systematic review and meta-analysis. Am. J. Alzheimers Dis. Other Demen. 30, 541–546 (2015).

  76. 76.

    Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016).

  77. 77.

    Mazaheri, F. et al. TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 18, 1186–1198 (2017).

  78. 78.

    Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016).

  79. 79.

    Mildner, A. et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J. Neurosci. 31, 11159–11171 (2011).

  80. 80.

    Condello, C., Yuan, P., Schain, A. & Grutzendler, J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6, 6176 (2015).

  81. 81.

    Bradshaw, E. M. et al. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat. Neurosci. 16, 848–850 (2013).

  82. 82.

    Heneka, M. T. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).

  83. 83.

    Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer’s disease. Nature 552, 355–361 (2017).

  84. 84.

    Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 212, 287–295 (2015).

  85. 85.

    Jay, T. R. et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 37, 637–647 (2017).

  86. 86.

    Lee, C. Y. et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s disease models. Neuron 97, 1032–1048 (2018).

  87. 87.

    Carrasquillo, M. M. et al. A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer’s disease risk and increased TREML1 and TREM2 brain gene expression. Alzheimers Dement. 13, 663–673 (2017).

  88. 88.

    Leyns, C. E. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl Acad. Sci. USA 114, 11524–11529 (2017).

  89. 89.

    Bemiller, S. M. et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol. Neurodegener. 12, 74 (2017).

  90. 90.

    Kober, D. L. et al. Neurodegenerative disease mutations in TREM2 reveal a f unctional surface and distinct loss-of-function mechanisms. eLife 5, e20391 (2016).

  91. 91.

    Sudom, A. et al. Molecular basis for the loss-of-function effects of the Alzheimer’s disease-associated R47H variant of the immune receptor TREM2. J. Biol. Chem. 293, 12634–12646 (2018).

  92. 92.

    Song, W. M. et al. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med. 215, 745–760 (2018).

  93. 93.

    Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C. & Sheng, M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91, 328–340 (2016).

  94. 94.

    Kleinberger, G. et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl Med. 6, 243ra286 (2014).

  95. 95.

    Ulrich, J. D., Ulland, T. K., Colonna, M. & Holtzman, D. M. Elucidating the role of TREM2 in Alzheimer’s disease. Neuron 94, 237–248 (2017).

  96. 96.

    Borroni, B. et al. Heterozygous TREM2 mutations in frontotemporal dementia. Neurobiol. Aging 35, 934 (2014).

  97. 97.

    Sirkis, D. W. et al. Rare TREM2 variants associated with Alzheimer’s disease display reduced cell surface expression. Acta Neuropathol. Commun. 4, 98 (2016).

  98. 98.

    Kleinberger, G. et al. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 36, 1837–1853 (2017).

  99. 99.

    Atagi, Y. et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290, 26043–26050 (2015).

  100. 100.

    Bailey, C. C., DeVaux, L. B. & Farzan, M. The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J. Biol. Chem. 290, 26033–26042 (2015).

  101. 101.

    Jendresen, C., Arskog, V., Daws, M. R. & Nilsson, L. N. The Alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway. J. Neuroinflammation 14, 59 (2017).

  102. 102.

    Zhao, Y. et al. TREM2 is a receptor for beta-amyloid that mediates microglial function. Neuron 97, 1023–1031 (2018).

  103. 103.

    Lessard, C. B. et al. High affinity interactions and signal transduction between Aβ oligomers and TREM2. Preprint at (2018).

  104. 104.

    Zhong, L. et al. Soluble TREM2 induces inflammatory responses and enhances microglial survival. J. Exp. Med. 214, 597–607 (2017).

  105. 105.

    Wu, K. et al. TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. J. Exp. Med. 212, 681–697 (2015).

  106. 106.

    Hsieh, C. L. et al. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J. Neurochem. 109, 1144–1156 (2009).

  107. 107.

    Zhong, L. et al. DAP12 stabilizes the C-terminal fragment of the triggering receptor expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro-inflammatory response. J. Biol. Chem. 290, 15866–15877 (2015).

  108. 108.

    Ohrfelt, A. et al. Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone. Mult. Scler. 22, 1587–1595 (2016).

  109. 109.

    Cooper-Knock, J. et al. A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis. Acta Neuropathol. Commun. 5, 23 (2017).

  110. 110.

    Suarez-Calvet, M. et al. sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer’s disease and associate with neuronal injury markers. EMBO Mol. Med. 8, 466–476 (2016).

  111. 111.

    Piccio, L. et al. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 131, 925–933 (2016).

  112. 112.

    Heslegrave, A. et al. Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer’s disease. Mol. Neurodegener. 11, 3 (2016).

  113. 113.

    Suarez-Calvet, M. et al. Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury. Sci. Transl Med. 8, 369ra178 (2016).

  114. 114.

    Henjum, K. et al. Cerebrospinal fluid soluble TREM2 in aging and Alzheimer’s disease. Alzheimers Res. Ther. 8, 17 (2016).

  115. 115.

    Voytyuk, I., De Strooper, B. & Chavez-Gutierrez, L. Modulation of γ- and β-secretases as early prevention against Alzheimer’s disease. Biol. Psychiatry 83, 320–327 (2018).

  116. 116.

    van Dyck, C. H. Anti-amyloid-beta monoclonal antibodies for Alzheimer’s disease: pitfalls and promise. Biol. Psychiatry 83, 311–319 (2018).

  117. 117.

    Strittmatter, S. M. Emerging mechanisms in Alzheimer’s disease and their therapeutic implications. Biol. Psychiatry 83, 298–299 (2018).

  118. 118.

    Griciuc, A. et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78, 631–643 (2013).

  119. 119.

    Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139, 1265–1281 (2016).

Download references


Review criteria

This Review serves as an overview of the current state of the field regarding triggering receptor expressed on myeloid cells 2 (TREM2) in Alzheimer disease (AD) pathogenesis, including the presentation of conflicting data. The authors primarily used PubMed to search the literature, focusing predominantly on the period between 2013, when TREM2 variants associated with an increased risk of AD were first reported, and the final submission date in February 2018. Supporting studies published before 2013 regarding AD and TREM2 were also reviewed. Search terms included “TREM2”, “TREM2 and Alzheimer’s disease”, “TREM2 and microglia”, “TREM2 and macrophages”, “Alzheimer’s disease” and “TREM2 and neurodegeneration”.

Author information


  1. University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    • Tyler K. Ulland
  2. Washington University School of Medicine, St Louis, MO, USA

    • Marco Colonna


  1. Search for Tyler K. Ulland in:

  2. Search for Marco Colonna in:


Both authors were involved in all aspects of the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Marco Colonna.

About this article

Publication history