Using Exome Sequencing to Reveal Mutations in TREM2 Presenting as a Frontotemporal Dementia–like Syndrome Without Bone Involvement
Open accessAbstract
OBJECTIVE: To identify new genes and risk factors associated with frontotemporal dementia (FTD). Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes. DESIGN: Whole-exome sequencing and whole-genome genotyping were performed in all patients. Genetic variants obtained from whole-exome sequencing were integrated with the data obtained from whole-genome genotyping. SETTING: Database of the Behavioral Neurology Outpatient Clinic of the Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. PATIENTS Forty-four Turkish patients with an FTD-like clinical diagnosis were included in the study. Relatives were screened when appropriate. MAIN OUTCOME MEASURE: Mutations in the triggering receptor expressed on myeloid cells 2 gene (TREM2). RESULTS: In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). None of these 3 patients had a typical clinical presentation of PLOSL: they presented with behavioral change and subsequent cognitive impairment and motor features but without any bone cysts or bone-associated phenotypes. Imaging showed white matter abnormalities as well as frontal atrophy in all 3 patients. CONCLUSIONS: Our results show that TREM2 is responsible for an unexpectedly high number of dementia cases in our cohort, suggesting that this gene should be taken into account when mutations in other dementia genes are excluded. Even for complex syndromes such as dementia, exome sequencing has proven to be a rapid and cost-effective tool to identify genetic mutations, allowing for the association of clinical phenotypes with unexpected molecular underpinnings.
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There is converging evidence for the role of neuroinflammation in neurodegenerative dementias, including frontotemporal dementia, from genetic associations, CSF, epidemiology, post-mortem tissue and animal models.
“In particular, there is converging evidence for the role of neuroinflammation in neurodegenerative dementias, including FTD, from genetic associations (Guerreiro et al., 2013; Rayaprolu et al., 2013; Broce et al., 2018), CSF (Sjogren et al., 2004; Woollacott et al., 2018), epidemiology (Miller et al., 2013, 2016), post-mortem tissue (Venneti et al., 2008; Lant et al., 2014) and animal models”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Guerreiro et al., 2013
Nonsense or missense mutations in TREM2 have been identified in several families with FTD.
“Nonsense or missense mutations in TREM2 have been identified in several families with FTD.343–345”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [344]
Homozygous TREM2 p.T66M mutation has been identified to cause FTD-like syndrome.
“Homozygous TREM2 p.T66M mutation has also been identified to cause FTD-like syndrome.344”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [344]
Further TREM2 variants such as R62H, H157Y, Q33X, T66M and Y38C are risk factors of Alzheimer's disease or other CNS diseases.
“In addition to the R47H variant, further TREM2 variants have been revealed to be risk factors of AD or other CNS diseases, such as R62H (8,20), H157Y (25), Q33X, T66M and Y38C (26,27).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [27]
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<i>TREM2</i>Variant p.R47H as a Risk Factor for Sporadic Amyotrophic Lateral Sclerosis
Cady, J., Koval, E. D., Benitez, B. A., Zaidman, C., Jockel-Balsarotti, J., Allred, P., Baloh, R. H., Ravits, J., Simpson, E., Appel, S. H., et al. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2013.6237 · Cited by 262 · see citing works
The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders
Carmona, S., Zahs, K., Wu, E., Dakin, K., Bras, J., & Guerreiro, R. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30232-1 · Cited by 244 · see citing works
Self-citationSuárez-Calvet, M., Araque Caballero, M. Á., Kleinberger, G., Bateman, R. J., Fagan, A. M., Morris, J. C., Levin, J., Danek, A., Ewers, M., Haass, C., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aag1767 · Cited by 272 · see citing works
Kleinberger, G., Brendel, M., Mracsko, E. Z., Wefers, B., Groeneweg, L., Xiang, X., Focke, C., Deußing, M., Suárez‐Calvet, M., Mazaheri, F., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201796516 · Cited by 244 · see citing works
USP18 lack in microglia causes destructive interferonopathy of the mouse brain
Goldmann, T., Zeller, N., Raasch, J., Kierdorf, K., Frenzel, K., Ketscher, L., Basters, A., Staszewski, O., Brendecke, S. M., Spiess, A., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490791 · Cited by 223 · see citing works
“…as Csf1r in hereditary diffuse leukoencephalopathy with spheroids (Rademakers et al , 2012), CD33 in Alzheimer’s disease (Hollingworth et al , 2011; Naj et al , 2011), Trem2 in frontotemporal dementia (Guerreiro et al , 2013), and Tnfrsf1a and Irf8 in multiple sclerosis (De Jager et al , 2009).”
Neuroinflammation: Ways in Which the Immune System Affects the Brain
Ransohoff, R. M., Schafer, D. P., Vincent, A. C., Blachère, N. E., & Bar‐Or, A. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0385-3 · Cited by 245 · see citing works
“the recent direct implication of microglia in neurodegeneration, some rare polymorphic structural variants of TREM2 were shown to be risk factors for Alzheimer disease [18, 19], while other TREM2 variants were found to be associated to frontotemporal dementia [20].”
Sayed, F. A., Telpoukhovskaia, M., Kodama, L., Li, Y., Zhou, Y., Le, D., Hauduc, A., Ludwig, C., Gao, F., Clelland, C., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811411115 · Cited by 229 · see citing works
“The rare R47H missense variant in TREM2 is associated with increased risk for tauopathies (2, 3, 26, 28) and hyperphosphorylation 20 40 60 0.”
BackgroundTREM2 and the neuroimmunology of Alzheimer's disease
Hickman, S. E., & El Khoury, J. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.11.021 · Cited by 221 · see citing works
“However, homozygous loss-of-function mutations in TREM2 are associated with an autosomal recessive form of early-onset dementia affecting brain and bone termed Nasu– Hakola disease [45] and with a form of frontotemporal dementia without bone involvement [46].”
BackgroundKober, D. L., Alexander-Brett, J. M., Karch, C. M., Cruchaga, C., Colonna, M., Holtzman, M. J., & Brett, T. J. (2016) · eLife · doi:10.7554/elife.20391 · Cited by 238 · see citing works
Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia
Brownjohn, P. W., Smith, J., Solanki, R., Lohmann, E., Houlden, H., Hardy, J., Dietmann, S., & Livesey, F. J. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.03.003 · Cited by 193 · see citing works
“We obtained fibroblasts from a patient homozygous for the TREM2 T66Mmutation, associated with an FTD-like condition (Guerreiro et al., 2013b) (T66M/T66M), two unaffected family members carrying a single copy of the T66Mmutation (wt/T66M), and a patient homozygous for the recently described…”
BackgroundSelf-citationLiu, W., Taso, O., Wang, R., Bayram, S., Graham, A. C., Garcia-Reitboeck, P., Mallach, A., Andrews, W. D., Piers, T. M., Botia, J. A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa209 · Cited by 214 · see citing works
“In addition to the R47H variant, further TREM2 variants have been revealed to be risk factors of AD or other CNS diseases, such as R62H (Jin et al. 2014; Sims et al. 2017), H157Y (Jiang et al. 2016), Q33X, T66M and Y38C (Guerreiro et al. 2013a; Guerreiro et al. 2013c).”
BackgroundSelf-citationMicroglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer’s Disease Genetics
Podleśny-Drabiniok, A., Marcora, E., & Goate, A. M. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.10.002 · Cited by 211 · see citing works
TREM2, microglia, and Alzheimer’s disease.
Qin, Q., Teng, Z., Liu, C., Li, Q., Yin, Y., & Tang, Y. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111438 · Cited by 219 · see citing works
Lill, C. M., Rengmark, A., Pihlstrøm, L., Fogh, I., Shatunov, A., Sleiman, P. M., Wang, L., Liu, T., Lassen, C. F., Meissner, E., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.12.009 · Cited by 205 · see citing works
“TREM2 was earlier reported to harbor autosomal-recessive mutations causing NasuHakola disease [8], a neurodegenerative disorder characterized by progressive presenile dementia and cystic bone lesions, and underlying familial FTLD [9].”
The Role of APOE and TREM2 in Alzheimer′s Disease—Current Understanding and Perspectives
Wolfe, C. M., Fitz, N. F., Nam, K. N., Lefterov, I. M., & Koldamova, R. P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010081 · Cited by 192 · see citing works
“1 in the TREM gene cluster near other TREM and TREM-like genes: TREML1, TREM2, TREML2, TREML3, TREML4, and TREM1 [68,69].”
BackgroundInfluentialTREM2 in CNS homeostasis and neurodegenerative disease
Painter, M. M., Atagi, Y., Liu, C.-C., Rademakers, R., Xu, H., Fryer, J. D., & Bu, G. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0040-9 · Cited by 169 · see citing works
“(non-NHD/PLOSL) clinical presentation [12].”
BackgroundInfluentialCuyvers, E., Bettens, K., Philtjens, S., Langenhove, T. V., Gijselinck, I., van der Zee, J., Engelborghs, S., Vandenbulcke, M., Dongen, J. V., Geerts, N., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.009 · Cited by 191 · see citing works
Innate immune activation in neurodegenerative diseases
Castro‐Gomez, S., & Heneka, M. T. (2024) · Immunity · doi:10.1016/j.immuni.2024.03.010 · Cited by 167 · see citing works
TREM2 is associated with the risk of Alzheimer's disease in Spanish population
Benitez, B. A., Cooper, B., Pastor, P., Jin, S.-C., Lorenzo, E., Cervantes, S., & Cruchaga, C. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.018 · Cited by 163 · see citing works
“However, 2 independent studies recently reported that a nonsynonymous variant in TREM2, rs75932628 (encoding R47H), is strongly associated with AD (Guerreiro et al., 2013a; Jonsson et al., 2012).”
InfluentialGarcia-Reitboeck, P., Phillips, A., Piers, T. M., Villegas-Llerena, C., Butler, M., Mallach, A., Rodrigues, C., Arber, C. E., Heslegrave, A., Zetterberg, H., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.094 · Cited by 162 · see citing works
Self-citationRyan, K. J., White, C. C., Patel, K. R., Xu, J., Olah, M., Replogle, J. M., Frangieh, M., Cimpean, M., Winn, P. A., McHenry, A., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aai7635 · Cited by 156 · see citing works
Guerreiro, R., Bilgic, B., Guven, G., Brás, J., Rohrer, J., Lohmann, E., Hanagasi, H., Gurvit, H., & Emre, M. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.06.005 · Cited by 158 · see citing works
“…cases with homozygous mutations in TREM2 have been described to present atypical phenotypes resembling behavioral variant frontotemporal dementia (bvFTD) and lacking stage (2) of the clinical picture described previously (Chouery et al., 2008; Giraldo et al., 2013; Guerreiro et al., 2013b).”
BackgroundResultInfluentialSelf-citationGenetics of Alzheimer's Disease
Guerreiro, R. J., & Hardy, J. (2014) · Neurotherapeutics · doi:10.1007/s13311-014-0295-9 · Cited by 158 · see citing works
“By performing autozygosity and exome sequencing analyses in Turkish dementia families we identified TREM2 homozygous mutations causing frontotemporal dementia [23].”
MethodSelf-citationGenetics of <scp>FTLD</scp> : overview and what else we can expect from genetic studies
Pottier, C., Ravenscroft, T. A., Sanchez‐Contreras, M., & Rademakers, R. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13622 · Cited by 148 · see citing works
“…a known cause of Nasu Hakola disease, have also been described in patients with atypical FTLD characterized by very young onset age, the presence of seizures and parkinsonism and extensive white matter lesions on brain imaging (Le Ber et al. 2014, Guerreiro et al. 2013a, Guerreiro et al. 2013b).”
TREM2 is associated with increased risk for Alzheimer’s disease in African Americans
Jin, S. C., Carrasquillo, M. M., Benitez, B. A., Skorupa, T., Carrell, D., Patel, D., Lincoln, S., Krishnan, S., Kachadoorian, M., Reitz, C., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0016-9 · Cited by 153 · see citing works
“its homozygous state in the proband of a Turkish pedigree with an FTD-like syndrome [16] and also observed in its”
BackgroundHeterozygous TREM2 mutations in frontotemporal dementia
Borroni, B., Ferrari, F., Galimberti, D., Nacmias, B., Barone, C., Bagnoli, S., Fenoglio, C., Piaceri, I., Archetti, S., Bonvicini, C., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.017 · Cited by 173 · see citing works
“Furthermore, in human control brain, TREM2 was expressed at higher levels in the hippocampus and neocortex (Guerreiro et al., 2013a), and this pattern of Table 2 In silico analyses of the amino acid changes found in the analyzed sample In silico software Q33X R47H R62H T66M D87N T96K R98W S116C…”
BackgroundInfluentialGiraldo, M., Lopera, F., Siniard, A. L., Corneveaux, J. J., Schrauwen, I., Carvajal, J., Muñoz, C., Ramirez-Restrepo, M., Gaiteri, C., Myers, A. J., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.02.016 · Cited by 147 · see citing works
“Recently, a variant in TREM2 (rs75932628) has also been implicated as a risk factor for both early-onset and late-onset Alzheimer's disease (Jonsson et al., 2012; Pottier et al., 2013; R. Guerreiro et al., 2012).”
BackgroundResultInfluentialThe clinical spectrum of sporadic and familial forms of frontotemporal dementia
Woollacott, I., & Rohrer, J. D. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13654 · Cited by 151 · see citing works
“Heterozygous TREM2 variants have recently been described as a risk factor for AD (Benitez et al. 2013; Guerreiro et al. 2013b; Jonsson et al. 2013; Pottier et al. 2013), but studies have been mixed as to whether this is also the case for FTD (Lattante et al. 2013; Rayaprolu et al. 2013; Borroni et…”
BackgroundSelf-citationPrice, B. R., Sudduth, T. L., Weekman, E. M., Johnson, S. N., Hawthorne, D., Woolums, A. E., & Wilcock, D. M. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01915-0 · Cited by 142 · see citing works
Cerebrospinal fluid soluble TREM2 in aging and Alzheimer’s disease
Henjum, K., Almdahl, I. S., Årskog, V., Minthon, L., Hansson, O., Fladby, T., & Nilsson, L. N. G. (2016) · Alzheimer s Research & Therapy · doi:10.1186/s13195-016-0182-1 · Cited by 141 · see citing works
“R47H] and frontotemporal dementia mutations [25] are most probably loss of function, resulting in reduced TREM2 cell surface localization and shedding [18].”
BackgroundKorvatska, O., Leverenz, J. B., Jayadev, S., McMillan, P., Kurtz, I., Guo, X., Rumbaugh, M., Matsushita, M., Girirajan, S., Dorschner, M. O., et al. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2015.0979 · Cited by 137 · see citing works
Soluble TREM2: Innocent bystander or active player in neurological diseases?
Filipello, F., Goldsbury, C., You, S. F., Locca, A., Karch, C. M., & Piccio, L. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105630 · Cited by 134 · see citing works
Aguzzi, A., & Zhu, C. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90605 · Cited by 122 · see citing works
Microglia-Mediated Neuroprotection, TREM2, and Alzheimer’s Disease: Evidence From Optical Imaging
Condello, C., Yuan, P., & Grutzendler, J. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.007 · Cited by 131 · see citing works
Götzl, J. K., Brendel, M., Werner, G., Parhizkar, S., Monasor, L. S., Kleinberger, G., Colombo, A.-V., Deußing, M., Wagner, M., Winkelmann, J., et al. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201809711 · Cited by 124 · see citing works
“…the progranulin (PGRN) protein; Baker et al, 2006; Cruts & Van Broeckhoven, 2008; Zhang et al, 2014; Gotzl et al, 2016; Lui et al, 2016) and TREM2 (Guerreiro et al, 2013; Jonsson & Stefansson, 2013; Jonsson et al, 2013; Rayaprolu et al, 2013; Borroni et al, 2014; Cuyvers et al, 2014; Ulrich et…”
BackgroundCheng, Q., Danao, J., Talreja, S., Wen, P. H., Yin, J., Sun, N., Li, C.-M., Chui, D., Tran, D. T., Koirala, S., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.001848 · Cited by 129 · see citing works
“More recently, variants in the TREM2 gene have been linked to increased risk for Alzheimer’s disease (AD) and other forms of dementia including frontotemporal dementia (5-7).”
BackgroundNeuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum
Bevan-Jones, W. R., Cope, T. E., Jones, P. S., Kaalund, S. S., Passamonti, L., Allinson, K., Green, O., Hong, Y. T., Fryer, T. D., Arnold, R., et al. (2020) · Brain · doi:10.1093/brain/awaa033 · Cited by 124 · see citing works
“…across the FTD spectrum, corroborating suggestions from epidemiological (Lant et al., 2014; Venneti et al., 2008), genetic (Broce et al., 2018; Guerreiro et al., 2013; Rayaprolu et al., 2013), imaging (Cagnin, Rossor, Sampson, MacKinnon, & Banati, 2004; Miyoshi et al., 2010) and animal…”
BackgroundPhenotypic Heterogeneity of Monogenic Frontotemporal Dementia
Benussi, A., Padovani, A., & Borroni, B. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00171 · Cited by 122 · see citing works
Parkinsonism, movement disorders and genetics in frontotemporal dementia
Baizabal-Carvallo, J. F., & Jankovic, J. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.14 · Cited by 121 · see citing works
Slattery, C. F., Beck, J. A., Harper, L., Adamson, G., Abdi, Z., Uphill, J., Campbell, T., Druyeh, R., Mahoney, C. J., Rohrer, J. D., et al. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.05.1751 · Cited by 119 · see citing works
Self-citationGenetic targeting of microglia
Wieghofer, P., Knobeloch, K., & Prinz, M. (2014) · Glia · doi:10.1002/glia.22727 · Cited by 116 · see citing works
Jiang, T., Tan, L., Zhu, X.-C., Zhou, J.-S., Cao, L., Tan, M.-S., Wang, H.-F., Chen, Q., Zhang, Y.-D., & Yu, J.-T. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.08.019 · Cited by 111 · see citing works
Ruiz, A., Dols-Icardo, O., Bullido, M. J., Pastor, P., Rodríguez-Rodríguez, E., López de Munain, A., de Pancorbo, M. M., Pérez-Tur, J., Álvarez, V., Antonell, A., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.08.011 · Cited by 118 · see citing works
Jiang, T., Yu, J., Zhu, X., & Tan, L. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8424-8 · Cited by 118 · see citing works
“Besides, Chouery and colleagues reported a homozygous mutation in the 5′ consensus donor splice site in intron 1 of TREM2 that led to early-onset dementia without bone cysts in a Lebanese family [27], and three homozygousmutations in TREM2 have recently been revealed in three Turkish probands with frontotemporal demen…”
BackgroundResultCentral nervous system myeloid cells as drug targets: current status and translational challenges
Biber, K. P. H., Möller, T., Boddeke, E., & Prinz, M. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.14 · Cited by 111 · see citing works
Fassler, M., Rappaport, M., Benaim, C., & George, J. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01980-5 · Cited by 110 · see citing works
“Whereas heterozygous variants in TREM2 are associated with AD [2, 3, 8], homozygous variants in TREM2 or its binding partner DAP12/TYROBP cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as Nasu-Hakola disease (NHD).”
BackgroundMicroglia in Alzheimer’s disease: A target for immunotherapy
Wang, S., & Colonna, M. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.mr0818-319r · Cited by 104 · see citing works
Radford, R. A. W., Morsch, M., Rayner, S. L., Cole, N. J., Pountney, D. L., & Chung, R. S. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00414 · Cited by 102 · see citing works
“Interestingly homozygous and compound heterozygous mutations are linked to a familial FTD-like disorder without bone involvement (Kaneko et al., 2010; Guerreiro et al., 2013; Borroni et al., 2014).”
Aminophospholipids are signal-transducing TREM2 ligands on apoptotic cells
Shirotani, K., Hori, Y., Yoshizaki, R., Higuchi, E., Colonna, M., Saito, T., Hashimoto, S., Saito, T., Saido, T. C., & Iwata, N. (2019) · Scientific Reports · doi:10.1038/s41598-019-43535-6 · Cited by 116 · see citing works
Homozygous TREM2 mutation in a family with atypical frontotemporal dementia
Ber, I. L., de Septenville, A. D., Guerreiro, R., Bras, J., Camuzat, A., Caroppo, P., Lattante, S., Couarch, P., Kabashi, E., Bouya-Ahmed, K., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.04.010 · Cited by 98 · see citing works
“…TREM2 mutations have been identified in rare families of Turkish and Colombian origin with autosomal recessive behavioral variant of frontotemporal lobar degeneration (FTLD) but without any clinical or radiological evidence of bone involvement (Giraldo et al., 2013; Guerreiro et al., 2013a, 2013b).”
BackgroundResultInfluentialSelf-citationJendresen, C., Årskog, V., Daws, M. R., & Nilsson, L. N. G. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0835-4 · Cited by 94 · see citing works
The Evolution of Genetics: Alzheimer’s and Parkinson’s Diseases
Singleton, A., & Hardy, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.05.040 · Cited by 91 · see citing works
Self-citationArreola, M. A., Soni, N., Crapser, J. D., Hohsfield, L. A., Elmore, M. R. P., Matheos, D. P., Wood, M. A., Swarup, V., Mortazavi, A., & Green, K. N. (2021) · Science Advances · doi:10.1126/sciadv.abg1601 · Cited by 89 · see citing works
Vps35-dependent recycling of Trem2 regulates microglial function
Yin, J., Liu, X., He, Q., Zhou, L., Yuan, Z., & Zhao, S. (2016) · Traffic · doi:10.1111/tra.12451 · Cited by 90 · see citing works
“Many mutations of Trem2 have been involved in several neurodegenerative diseases.(6,10,13,41,42) Recently, 2 independent groups investigated how Trem2 missense mutations affected Trem2 func-”
A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature
Dardiotis, E., Siokas, V., Pantazi, E., Dardioti, M., Rikos, D., Xiromerisiou, G., Markou, A., Papadimitriou, D. A., Speletas, M. G., & Hadjigeorgiou, G. M. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.01.015 · Cited by 89 · see citing works
Park, J., Ji, I. J., An, H. J., Kang, M., Kang, S., Kim, D., & Yoon, S. (2015) · Traffic · doi:10.1111/tra.12264 · Cited by 88 · see citing works
“Recently, several TREM2 mutations have also been reported to cause a fronto-temporal dementia (FTD)-like syndrome without bone pathology (7,8).”
BackgroundOligodendrocytes in Alzheimer’s disease pathophysiology
Kedia, S., & Simons, M. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-01873-x · Cited by 86 · see citing works
“One example is TREM2 , where rare loss-of-function genetic variants have been identified in the coding region of a gene exclusively expressed in microglia, thereby tripling the risk of AD 68,69 .”
Shifting paradigms: The central role of microglia in Alzheimer’s disease
Schwabe, T., Srinivasan, K., & Rhinn, H. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104962 · Cited by 84 · see citing works
“1% of the general population, was found to be associated with AD risk through genome-wide scans and targeted sequencing or imputation (Guerreiro et al., 2013; Jonsson et al., 2013).”
BackgroundThe Role of Microglia in Sporadic Alzheimer’s Disease
Streit, W. J., Khoshbouei, H., & Bechmann, I. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201248 · Cited by 84 · see citing works
“…a rare coding variant in the TREM2 gene is present in approximatively 0.1% of the general population found to be associated with increased AD risk [6, 7], consistent with prior work showing that TREM2 is among the highest upregulated mRNAs and the protein colocalizes with microglia at plaques in…”
Influential
- Authors
- Guerreiro, R. J., Lohmann, E., Brás, J. M., Gibbs, J. R., Rohrer, J. D., Gurunlian, N., Dursun, B., Bilgic, B., Hanagasi, H., Gurvit, H., Emre, M., Singleton, A., & Hardy, J.
- Affiliations
- National Institutes of Health (US)
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2013-01-01
- Volume
- 70
- Issue
- 1
- Pages
- 78
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC4001789
- OpenAlex
- W1984557585
- Cited by
- 374
- References
- 27
- Citations by year
- 2026: 18 · 2025: 23 · 2024: 20 · 2023: 17 · 2022: 12 · 2021: 39 · 2020: 34 · 2019: 22 · 2018: 32 · 2017: 37 · 2016: 29 · 2015: 40 · 2014: 26 · 2013: 21 · 2012: 3
- FWCI
- 27.37
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (089698)
- National Institutes of Health
- National Institute on Aging (Z01AG000950)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- TREM2, frontotemporal dementia, homozygous mutation, genetic diagnosis, white matter abnormalities, behavior change, cognitive impairment, exome sequencing, Turkish patients
- MeSH terms
- Adult, Humans, Male, Membrane Glycoproteins, Mutation, Receptors, Immunologic, Risk Factors, Syndrome, Frontotemporal Dementia, Exome
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