{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T20:59:41Z","timestamp":1770065981266,"version":"3.49.0"},"reference-count":94,"publisher":"IMR Press","issue":"4","license":[{"start":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T00:00:00Z","timestamp":1654041600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>Background: Triggering receptor expressed on myeloid cells 2 (TREM2) is an important modulator of innate immune responses. In the human brain, TREM2 is primarily expressed on microglia and is involved in cell survival, phagocytosis, and regulation of inflammation. TREM2 dysfunction has been linked to the pathogenesis of various neurodegenerative diseases including Alzheimer\u2019s disease (AD). Rare coding variants of the TREM2 gene have been reported to modulate AD risk in several populations, however, data on their association with susceptibility to AD in the Slovak population have been missing. Methods: We have analyzed 10 non-synonymous coding variants located in TREM2 exon 2 by direct sequencing in 270 late-onset Alzheimer\u2019s disease (LOAD) patients and 331 controls. Results: Four out of 10 TREM2 mutant variants have been identified in the analyzed groups, namely rs75932628 C &gt; T (R47H), rs142232675 C &gt; T (D87N), rs143332484 C &gt; T (R62H), and rs2234253 G &gt; T (T96K). R47H was found only in the AD group, while T96K was present only in the controls. Although no significant association between TREM2 coding variants and LOAD susceptibility has been detected, the observed odds ratio (OR) of 3.69 for R47H carriers suggests an increased risk of LOAD for this variant in the Slovak population. Moreover, we also found a higher OR for the rs143332484-T allele in APOE\u03b54 non-carriers (1.99) when compared to APOE\u03b54 carriers (0.62). Conclusions: Our results suggest an impact of specific TREM2 rare coding variants on AD risk in the Slovak population.<\/jats:p>","DOI":"10.31083\/j.jin2104105","type":"journal-article","created":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T08:17:39Z","timestamp":1654157859000},"source":"Crossref","is-referenced-by-count":5,"title":["TREM2 coding variants in Slovak Alzheimer's disease patients"],"prefix":"10.31083","volume":"21","author":[{"given":"Vladimira","family":"Durmanova","sequence":"first","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, 81108 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juraj","family":"Javor","sequence":"first","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, 81108 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuzana","family":"Parnicka","sequence":"first","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, 81108 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Minarik","sequence":"first","affiliation":[{"name":"Medirex Group Academy, Ltd, 82016 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agata","family":"Ocenasova","sequence":"first","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, 81108 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbora","family":"Vaseckova","sequence":"first","affiliation":[{"name":"Psychiatry Outpatient Clinic, University Hospital and Policlinic the Brothers of Saint John of God, 81106 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iliana","family":"Kiralyova","sequence":"first","affiliation":[{"name":"Care Centre Centrum MEMORY, 85103 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanislav","family":"Sutovsky","sequence":"first","affiliation":[{"name":"1st Department of Neurology, Faculty of Medicine, Comenius University in Bratislava and University Hospital, 81367 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Petrovic","sequence":"first","affiliation":[{"name":"Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava and University Hospital, 81369 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivana","family":"Shawkatova","sequence":"first","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, 81108 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"16242","published-online":{"date-parts":[[2022,6,1]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Bouchon A, Hern\u00e1ndez-Munain C, Cella M, Colonna M. A Dap12-Mediated Pathway Regulates Expression of Cc Chemokine Receptor 7 and Maturation of Human Dendritic Cells. Journal of Experimental Medicine. 2001; 194: 1111\u20131122.","DOI":"10.1084\/jem.194.8.1111"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"Cella M, Buonsanti C, Strader C, Kondo T, Salmaggi A, Colonna M. Impaired differentiation of osteoclasts in TREM-2-deficient individuals. Journal of Experimental Medicine. 2003; 198: 645\u2013651.","DOI":"10.1084\/jem.20022220"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Colonna M. TREMs in the immune system and beyond. Nature Reviews Immunology. 2003; 3: 445\u2013453.","DOI":"10.1038\/nri1106"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"Allcock RJN, Barrow AD, Forbes S, Beck S, Trowsdale J. The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44. European Journal of Immunology. 2003; 33: 567\u2013577.","DOI":"10.1002\/immu.200310033"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"Daws MR, Lanier LL, Seaman WE, Ryan JC. Cloning and characterization of a novel mouse myeloid DAP12-associated receptor family. European Journal of Immunology. 2001; 31: 783\u2013791.","DOI":"10.1002\/1521-4141(200103)31:3<783::AID-IMMU783>3.0.CO;2-U"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Atagi Y, Liu C, Painter MM, Chen X, Verbeeck C, Zheng H, et al. Apolipoprotein E is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Journal of Biological Chemistry. 2015; 290: 26043\u201326050.","DOI":"10.1074\/jbc.M115.679043"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"Bailey CC, DeVaux LB, Farzan M. The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E. Journal of Biological Chemistry. 2016; 290: 26033\u201326042.","DOI":"10.1074\/jbc.M115.677286"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M. TREM2 Binds to Apolipoproteins, Including APOE and CLUAPOJ, and thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron. 2016; 91: 328\u2013340.","DOI":"10.1016\/j.neuron.2016.06.015"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Kober DL, Brett TJ. TREM2-Ligand Interactions in Health and Disease. Journal of Molecular Biology. 2017; 429: 1607\u20131629.","DOI":"10.1016\/j.jmb.2017.04.004"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"Colonna M, Wang Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nature Reviews. Neuroscience. 2016; 17: 201\u2013207.","DOI":"10.1038\/nrn.2016.7"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"Hamerman JA, Jarjoura JR, Humphrey MB, Nakamura MC, Seaman WE, Lanier LL. Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. Journal of Immunology. 2006; 177: 2051\u20132055.","DOI":"10.4049\/jimmunol.177.4.2051"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"Gao X, Dong Y, Liu Z, Niu B. Silencing of triggering receptor expressed on myeloid cells-2 enhances the inflammatory responses of alveolar macrophages to lipopolysaccharide. Molecular Medicine Reports. 2014; 7: 921\u2013926.","DOI":"10.3892\/mmr.2013.1268"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"Zhong L, Chen X, Zhang Z, Wang Z, Shi X, Xu K, 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. Journal of Biological Chemistry. 2015; 290: 15866\u201315877.","DOI":"10.1074\/jbc.M115.645986"},{"key":"ref14","doi-asserted-by":"crossref","unstructured":"Takahashi K, Rochford CDP, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. Journal of Experimental Medicine. 2005; 201: 647\u2013657.","DOI":"10.1084\/jem.20041611"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC, et al. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. Journal of Neurochemistry. 2009; 109: 1144\u20131156.","DOI":"10.1111\/j.1471-4159.2009.06042.x"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"Liu W, Taso O, Wang R, Bayram S, Graham AC, Garcia-Reitboeck P, et al. TREM2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions. Human Molecular Genetics. 2020; 29: 3224\u20133248.","DOI":"10.1093\/hmg\/ddaa209"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"Liu G, Liu Y, Jiang Q, Jiang Y, Feng R, Zhang L, et al. Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson\u2019s Disease Susceptibility. Molecular Neurobiology. 2018; 53: 4931\u20134938.","DOI":"10.1007\/s12035-015-9416-7"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"Cady J, Koval ED, Benitez BA, Zaidman C, Jockel-Balsarotti J, Allred P, et al. TREM2Variant p.R47H as a Risk Factor for Sporadic Amyotrophic Lateral Sclerosis. JAMA Neurology. 2014; 71: 449.","DOI":"10.1001\/jamaneurol.2013.6237"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"Kawabori M, Kacimi R, Kauppinen T, Calosing C, Kim JY, Hsieh CL, et al. Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke. Journal of Neuroscience. 2015; 35: 3384\u20133396.","DOI":"10.1523\/JNEUROSCI.2620-14.2015"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"Backes FN, de Souza A, Bianchin MM. Biomarkers in the prognostic evaluation of ischemic stroke: is there benefit in the measurements of TREM-1 and TREM-2 in the acute phase? Clinical Biochemistry. 2021; 98: 10\u201316.","DOI":"10.1016\/j.clinbiochem.2021.07.016"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"Saber M, Kokiko-Cochran O, Puntambekar SS, Lathia JD, Lamb BT. Triggering Receptor Expressed on Myeloid Cells 2 Deficiency Alters Acute Macrophage Distribution and Improves Recovery after Traumatic Brain Injury. Journal of Neurotrauma. 2018; 34: 423\u2013435.","DOI":"10.1089\/neu.2016.4401"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"Celarain N, S\u00e1nchez-Ruiz de Gordoa J, Zelaya MV, Rold\u00e1n M, Larumbe R, Pulido L, et al. TREM2 upregulation correlates with 5-hydroxymethycytosine enrichment in Alzheimer\u2019s disease hippocampus. Clinical Epigenetics. 2016; 8: 37.","DOI":"10.1186\/s13148-016-0202-9"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Ma L, Allen M, Sakae N, Ertekin-Taner N, Graff-Radford NR, Dickson DW, et al. Expression and processing analyses of wild type and p.R47H TREM2 variant in Alzheimer\u2019s disease brains. Molecular Neurodegeneration. 2017; 11: 72.","DOI":"10.1186\/s13024-016-0137-9"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"Perez SE, Nadeem M, He B, Miguel JC, Malek-Ahmadi MH, Chen K, et al. Neocortical and hippocampal TREM2 protein levels during the progression of Alzheimer\u2019s disease. Neurobiology of Aging. 2017; 54: 133\u2013143.","DOI":"10.1016\/j.neurobiolaging.2017.02.012"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"Liu D, Cao B, Zhao Y, Huang H, McIntyre RS, Rosenblat JD, et al. Soluble TREM2 changes during the clinical course of Alzheimer\u2019s disease: a meta-analysis. Neuroscience Letters. 2019; 686: 10\u201316.","DOI":"10.1016\/j.neulet.2018.08.038"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"Yeh FL, Hansen DV, Sheng M. TREM2, Microglia, and Neurodegenerative Diseases. Trends in Molecular Medicine. 2018; 23: 512\u2013533.","DOI":"10.1016\/j.molmed.2017.03.008"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer\u2019s disease model. Cell. 2015; 160: 1061\u20131071.","DOI":"10.1016\/j.cell.2015.01.049"},{"key":"ref28","doi-asserted-by":"crossref","unstructured":"Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al. TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy. Neuron. 2017; 90: 724\u2013739.","DOI":"10.1016\/j.neuron.2016.05.003"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"Zhao Y, Wu X, Li X, Jiang L, Gui X, Liu Y, et al. TREM2 is a Receptor for \u03b2-Amyloid that Mediates Microglial Function. Neuron. 2018; 97: 1023\u20131031.","DOI":"10.1016\/j.neuron.2018.01.031"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"Zhong L, Wang Z, Wang D, Wang Z, Martens YA, Wu L, et al. Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2) Molecular Neurodegeneration. 2018; 13: 15.","DOI":"10.1186\/s13024-018-0247-7"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"Kober DL, Stuchell-Brereton MD, Kluender CE, Dean HB, Strickland MR, Steinberg DF, et al. Functional insights from biophysical study of TREM2 interactions with apoE and A\u03b21-42. To be published in Alzheimer\u2019s & Dementia. 2020. [Preprint].","DOI":"10.1101\/2020.02.24.963264"},{"key":"ref32","doi-asserted-by":"crossref","unstructured":"Zheng H, Jia L, Liu C, Rong Z, Zhong L, Yang L, et al. TREM2 Promotes Microglial Survival by Activating Wnt\/\u03b2-Catenin Pathway. Journal of Neuroscience. 2017; 37: 1772\u20131784.","DOI":"10.1523\/JNEUROSCI.2459-16.2017"},{"key":"ref33","doi-asserted-by":"crossref","unstructured":"Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. Journal of Experimental Medicine. 2016; 213: 667\u2013675.","DOI":"10.1084\/jem.20151948"},{"key":"ref34","doi-asserted-by":"crossref","unstructured":"Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer\u2019s disease. New England Journal of Medicine. 2013; 368: 117\u2013127.","DOI":"10.1056\/NEJMoa1211851"},{"key":"ref35","doi-asserted-by":"crossref","unstructured":"Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer\u2019s disease. New England Journal of Medicine. 2013; 368: 107\u2013116.","DOI":"10.1056\/NEJMoa1211103"},{"key":"ref36","doi-asserted-by":"crossref","unstructured":"Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families. Science. 1993; 261: 921\u2013923.","DOI":"10.1126\/science.8346443"},{"key":"ref37","doi-asserted-by":"crossref","unstructured":"Li R, Wang X, He P. The most prevalent rare coding variants of TREM2 conferring risk of Alzheimer\u2019s disease: A systematic review and meta-analysis. Experimental and Therapeutic Medicine. 2021; 21: 347.","DOI":"10.3892\/etm.2021.9778"},{"key":"ref38","doi-asserted-by":"crossref","unstructured":"Benitez BA, Cooper B, Pastor P, Jin S, Lorenzo E, Cervantes S, et al. TREM2 is associated with the risk of Alzheimer\u2019s disease in Spanish population. Neurobiology of Aging. 2013; 34: e15\u2013e17.","DOI":"10.1016\/j.neurobiolaging.2012.12.018"},{"key":"ref39","doi-asserted-by":"crossref","unstructured":"Hooli BV, Parrado AR, Mullin K, Yip W, Liu T, Roehr JT, et al. The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk. Neurology. 2014; 83: 1353\u20131358.","DOI":"10.1212\/WNL.0000000000000855"},{"key":"ref40","doi-asserted-by":"crossref","unstructured":"Ruiz A, Dols-Icardo O, Bullido MJ, Pastor P, Rodr\u00edguez-Rodr\u00edguez E, L\u00f3pez de Munain A, et al. Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer\u2019s disease and frontotemporal dementia. Neurobiology of Aging. 2014; 35: e1\u2013e4.","DOI":"10.1016\/j.neurobiolaging.2013.08.011"},{"key":"ref41","doi-asserted-by":"crossref","unstructured":"Slattery CF, Beck JA, Harper L, Adamson G, Abdi Z, Uphill J, et al. R47H TREM2 variant increases risk of typical early-onset Alzheimer\u2019s disease but not of prion or frontotemporal dementia. Alzheimer\u2019s & Dementia. 2014; 10: 602\u2013608.","DOI":"10.1016\/j.jalz.2014.05.1751"},{"key":"ref42","doi-asserted-by":"crossref","unstructured":"Finelli D, Rollinson S, Harris J, Jones M, Richardson A, Gerhard A, et al. TREM2 analysis and increased risk of Alzheimer\u2019s disease. Neurobiology of Aging. 2015; 36: e9\u2013e13.","DOI":"10.1016\/j.neurobiolaging.2014.08.001"},{"key":"ref43","doi-asserted-by":"crossref","unstructured":"Rosenthal SL, Bamne MN, Wang X, Berman S, Snitz BE, Klunk WE, et al. More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer\u2019s disease risk. Neurobiology of Aging. 2016; 36: e21\u2013e26.","DOI":"10.1016\/j.neurobiolaging.2015.04.012"},{"key":"ref44","doi-asserted-by":"crossref","unstructured":"Lill CM, Rengmark A, Pihlstr\u00f8m L, Fogh I, Shatunov A, Sleiman PM, et al. The role of TREM2 R47H as a risk factor for Alzheimer\u2019s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson\u2019s disease. Alzheimer\u2019s & Dementia. 2016; 11: 1407\u20131416.","DOI":"10.1016\/j.jalz.2014.12.009"},{"key":"ref45","doi-asserted-by":"crossref","unstructured":"Korvatska O, Leverenz JB, Jayadev S, McMillan P, Kurtz I, Guo X, et al. R47H Variant of TREM2 Associated with Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study. JAMA Neurology. 2015; 72: 920\u2013927.","DOI":"10.1001\/jamaneurol.2015.0979"},{"key":"ref46","doi-asserted-by":"crossref","unstructured":"Lu Y, Liu W, Wang X. TREM2 variants and risk of Alzheimer\u2019s disease: a meta-analysis. Neurological Sciences. 2015; 36: 1881\u20131888.","DOI":"10.1007\/s10072-015-2274-2"},{"key":"ref47","doi-asserted-by":"crossref","unstructured":"Jin SC, Carrasquillo MM, Benitez BA, Skorupa T, Carrell D, Patel D, et al. TREM2 is associated with increased risk for Alzheimer\u2019s disease in African Americans. Molecular Neurodegeneration. 2015; 10: 19.","DOI":"10.1186\/s13024-015-0016-9"},{"key":"ref48","doi-asserted-by":"crossref","unstructured":"Arboleda-Bustos CE, Ortega-Rojas J, Mahecha MF, Arboleda G, V\u00e1squez R, Pardo R, et al. The p.R47H Variant of TREM2 Gene is Associated with Late-onset Alzheimer Disease in Colombian Population. Alzheimer Disease and Associated Disorders. 2019; 32: 305\u2013308.","DOI":"10.1097\/WAD.0000000000000275"},{"key":"ref49","doi-asserted-by":"crossref","unstructured":"Yu J, Jiang T, Wang Y, Wang H, Zhang W, Hu N, et al. Triggering receptor expressed on myeloid cells 2 variant is rare in late-onset Alzheimer\u2019s disease in Han Chinese individuals. Neurobiology of Aging. 2014; 35: e1\u2013e3.","DOI":"10.1016\/j.neurobiolaging.2013.10.075"},{"key":"ref50","doi-asserted-by":"crossref","unstructured":"Ma J, Zhou Y, Xu J, Liu X, Wang Y, Deng Y, et al. Association study of TREM2 polymorphism rs75932628 with late-onset Alzheimer\u2019s disease in Chinese Han population. Neurological Research. 2015; 36: 894\u2013896.","DOI":"10.1179\/1743132814Y.0000000376"},{"key":"ref51","doi-asserted-by":"crossref","unstructured":"Miyashita A, Wen Y, Kitamura N, Matsubara E, Kawarabayashi T, Shoji M, et al. Lack of genetic association between TREM2 and late-onset Alzheimer\u2019s disease in a Japanese population. Journal of Alzheimer\u2019s Disease. 2015; 41: 1031\u20131038.","DOI":"10.3233\/JAD-140225"},{"key":"ref52","doi-asserted-by":"crossref","unstructured":"Huang M, Wang D, Xu Z, Xu Y, Xu X, Ma Y, et al. Lack of Genetic Association between TREM2 and Alzheimer\u2019s Disease in East Asian Population. American Journal of Alzheimer\u2019s Disease & other Dementiasr. 2015; 30: 541\u2013546.","DOI":"10.1177\/1533317515577128"},{"key":"ref53","doi-asserted-by":"crossref","unstructured":"Wang P, Guo Q, Zhou Y, Chen K, Xu Y, Ding D, et al. Lack of association between triggering receptor expressed on myeloid cells 2 polymorphism rs75932628 and late-onset Alzheimer\u2019s disease in a Chinese Han population. Psychiatric Genetics. 2018; 28: 16\u201318.","DOI":"10.1097\/YPG.0000000000000188"},{"key":"ref54","doi-asserted-by":"crossref","unstructured":"Zhang B, Li R, Zhang Y, Gao X. Differential role of triggering receptors expressed on myeloid cells 2 R47H in 3 neurodegenerative diseases based on a systematic review and meta-analysis. Medicine. 2020; 99: e18921.","DOI":"10.1097\/MD.0000000000018921"},{"key":"ref55","doi-asserted-by":"crossref","unstructured":"Cuyvers E, Bettens K, Philtjens S, Van Langenhove T, Gijselinck I, van der Zee J, et al. Investigating the role of rare heterozygous TREM2 variants in Alzheimer\u2019s disease and frontotemporal dementia. Neurobiology of Aging. 2014; 35: e11\u2013e19.","DOI":"10.1016\/j.neurobiolaging.2013.09.009"},{"key":"ref56","doi-asserted-by":"crossref","unstructured":"Ghani M, Sato C, Kakhki EG, Gibbs JR, Traynor B, St George-Hyslop P, et al. Mutation analysis of the MS4a and TREM gene clusters in a case-control Alzheimer\u2019s disease data set. Neurobiology of Aging. 2017; 42: e7\u2013e13.","DOI":"10.1016\/j.neurobiolaging.2016.03.009"},{"key":"ref57","doi-asserted-by":"crossref","unstructured":"Jiang T, Hou J, Gao Q, Yu J, Zhou J, Zhao H, et al. TREM2 p.H157Y Variant and the Risk of Alzheimer\u2019s Disease: a Meta-Analysis Involving 14,510 Subjects. Current Neurovascular Research. 2016; 13: 318\u2013320.","DOI":"10.2174\/1567202613666160808095530"},{"key":"ref58","doi-asserted-by":"crossref","unstructured":"Peplonska B, Berdynski M, Mandecka M, Barczak A, Kuzma-Kozakiewicz M, Barcikowska M, et al. TREM2 variants in neurodegenerative disorders in the Polish population. Homozygosity and compound heterozygosity in FTD patients. Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration. 2019; 19: 407\u2013412.","DOI":"10.1080\/21678421.2018.1451894"},{"key":"ref59","doi-asserted-by":"crossref","unstructured":"Dalmasso MC, Brusco LI, Olivar N, Muchnik C, Hanses C, Milz E, et al. Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer\u2019s disease. Translational Psychiatry. 2019; 9: 55.","DOI":"10.1038\/s41398-019-0394-9"},{"key":"ref60","doi-asserted-by":"crossref","unstructured":"Zhou S, Tan C, Hou X, Cao X, Tan L, Yu J. TREM2 Variants and Neurodegenerative Diseases: a Systematic Review and Meta-Analysis. Journal of Alzheimer\u2019s Disease. 2019; 68: 1171\u20131184.","DOI":"10.3233\/JAD-181038"},{"key":"ref61","doi-asserted-by":"crossref","unstructured":"Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, et al. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. ELife. 2016; 5: e20391.","DOI":"10.7554\/eLife.20391"},{"key":"ref62","doi-asserted-by":"crossref","unstructured":"Song WM, Joshita S, Zhou Y, Ulland TK, Gilfillan S, Colonna M. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. Journal of Experimental Medicine. 2018; 215: 745\u2013760.","DOI":"10.1084\/jem.20171529"},{"key":"ref63","doi-asserted-by":"crossref","unstructured":"Korvatska O, Kiianitsa K, Ratushny A, Matsushita M, Beeman N, Chien WM, et al. Triggering Receptor Expressed on Myeloid Cell 2 R47H Exacerbates Immune Response in Alzheimer\u2019s Disease Brain. Frontiers in Immunology. 2020; 11: 559342.","DOI":"10.3389\/fimmu.2020.559342"},{"key":"ref64","doi-asserted-by":"crossref","unstructured":"Vilalta A, Zhou Y, Sevalle J, Griffin JK, Satoh K, Allendorf DH, et al. Wild-type s TREM2 blocks a\u03b2 aggregation and neurotoxicity, but the Alzheimer\u2019s R47H mutant increases a\u03b2 aggregation. Journal of Biological Chemistry. 2021; 296: 100631.","DOI":"10.1016\/j.jbc.2021.100631"},{"key":"ref65","doi-asserted-by":"crossref","unstructured":"McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer\u2019s disease: Report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer\u2019s Disease. Neurology. 1984; 34: 939\u2013939.","DOI":"10.1212\/WNL.34.7.939"},{"key":"ref66","doi-asserted-by":"crossref","unstructured":"Nasreddine ZS, Phillips NA, B\u00e9dirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. Journal of the American Geriatrics Society. 2005; 53: 695\u2013699.","DOI":"10.1111\/j.1532-5415.2005.53221.x"},{"key":"ref67","doi-asserted-by":"crossref","unstructured":"Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Research. 1988; 16: 1215.","DOI":"10.1093\/nar\/16.3.1215"},{"key":"ref68","doi-asserted-by":"crossref","unstructured":"Durmanova V, Parnicka Z, Javor J, Minarik G, Vrazda L, Vaseckova B, et al. A Novel Association of Polymorphism in the ITGA4 Gene Encoding the VLA-4 \u03b14 Subunit with Increased Risk of Alzheimer\u2019s Disease. Mediators of Inflammation. 2018; 2018: 7623823.","DOI":"10.1155\/2018\/7623823"},{"key":"ref69","doi-asserted-by":"crossref","unstructured":"Sol\u00e9 X, Guin\u00f3 E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006; 22: 1928\u20131929.","DOI":"10.1093\/bioinformatics\/btl268"},{"key":"ref70","doi-asserted-by":"crossref","unstructured":"Cortina-Borja M, Smith AD, Combarros O, Lehmann DJ. The synergy factor: a statistic to measure interactions in complex diseases. BMC Research Notes. 2009; 2: 105.","DOI":"10.1186\/1756-0500-2-105"},{"key":"ref71","doi-asserted-by":"crossref","unstructured":"Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta-analysis of diagnosed Alzheimer\u2019s disease identifies new risk loci and implicates A\u03b2, tau, immunity and lipid processing. Nature Genetics. 2019; 51: 414\u2013430.","DOI":"10.1038\/s41588-019-0358-2"},{"key":"ref72","doi-asserted-by":"crossref","unstructured":"de Rojas I, Moreno-Grau S, Tesi N, Grenier-Boley B, Andrade V, Jansen IE, et al. Common variants in Alzheimer\u2019s disease and risk stratification by polygenic risk scores. Nature Communications. 2021; 12: 3417.","DOI":"10.1038\/s41467-021-22491-8"},{"key":"ref73","doi-asserted-by":"crossref","unstructured":"Pottier C, Wallon D, Rousseau S, Rovelet-Lecrux A, Richard A, Rollin-Sillaire A, et al. TREM2 R47H variant as a risk factor for early-onset Alzheimer\u2019s disease. Journal of Alzheimer\u2019s Disease. 2013; 35: 45\u201349.","DOI":"10.3233\/JAD-122311"},{"key":"ref74","doi-asserted-by":"crossref","unstructured":"Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G, et al. Contribution to Alzheimer\u2019s disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiology of Aging. 2018; 59: e1\u2013e9.","DOI":"10.1016\/j.neurobiolaging.2017.07.001"},{"key":"ref75","doi-asserted-by":"crossref","unstructured":"Mehrjoo Z, Najmabadi A, Abedini SS, Mohseni M, Kamali K, Najmabadi H, et al. Association Study of the TREM2 Gene and Identification of a Novel Variant in Exon 2 in Iranian Patients with Late-Onset Alzheimer\u2019s Disease. Medical Principles and Practice. 2016; 24: 351\u2013354.","DOI":"10.1159\/000430842"},{"key":"ref76","doi-asserted-by":"crossref","unstructured":"Roussos P, Katsel P, Fam P, Tan W, Purohit DP, Haroutunian V. The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer\u2019s dementia. Alzheimer\u2019s & Dementia. 2016; 11: 1163\u20131170.","DOI":"10.1016\/j.jalz.2014.10.013"},{"key":"ref77","doi-asserted-by":"crossref","unstructured":"Sirkis DW, Bonham LW, Aparicio RE, Geier EG, Ramos EM, Wang Q, et al. Rare TREM2 variants associated with Alzheimer\u2019s disease display reduced cell surface expression. Acta Neuropathologica Communications. 2017; 4: 98.","DOI":"10.1186\/s40478-016-0367-7"},{"key":"ref78","doi-asserted-by":"crossref","unstructured":"Ayer AH, Wojta K, Ramos EM, Dokuru D, Chen JA, Karydas AM, et al. Frequency of the TREM2 R47H Variant in Various Neurodegenerative Disorders. Alzheimer Disease & Associated Disorders. 2019; 33: 327\u2013330.","DOI":"10.1097\/WAD.0000000000000339"},{"key":"ref79","doi-asserted-by":"crossref","unstructured":"Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer\u2019s disease. Nature Genetics. 2017; 49: 1373\u20131384.","DOI":"10.1038\/ng.3916"},{"key":"ref80","doi-asserted-by":"crossref","unstructured":"Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer\u2019s disease risk. Nature Genetics. 2019; 51: 404\u2013413.","DOI":"10.1038\/s41588-018-0311-9"},{"key":"ref81","doi-asserted-by":"crossref","unstructured":"Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer\u2019s disease. Nature Genetics. 2021; 53: 1276\u20131282.","DOI":"10.1038\/s41588-021-00921-z"},{"key":"ref82","doi-asserted-by":"crossref","unstructured":"Kleinberger G, Yamanishi Y, Su\u00e1rez-Calvet M, Czirr E, Lohmann E, Cuyvers E, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Science Translational Medicine. 2014; 6: 243ra86.","DOI":"10.1126\/scitranslmed.3009093"},{"key":"ref83","doi-asserted-by":"crossref","unstructured":"Cheng-Hathaway PJ, Reed-Geaghan EG, Jay TR, Casali BT, Bemiller SM, Puntambekar SS, et al. The TREM2 R47H variant confers loss-of-function-like phenotypes in Alzheimer\u2019s disease. Molecular Neurodegeneration. 2018; 13: 29.","DOI":"10.1186\/s13024-018-0262-8"},{"key":"ref84","doi-asserted-by":"crossref","unstructured":"Song W, Hooli B, Mullin K, Jin SC, Cella M, Ulland TK, et al. Alzheimer\u2019s disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimer\u2019s & Dementia. 2017; 13: 381\u2013387.","DOI":"10.1016\/j.jalz.2016.07.004"},{"key":"ref85","doi-asserted-by":"crossref","unstructured":"Jadhav VS, Lin PBC, Pennington T, Di Prisco GV, Jannu AJ, Xu G, et al. TREM2 Y38C mutation and loss of TREM2 impairs neuronal synapses in adult mice. Molecular Neurodegeneration. 2020; 15: 62.","DOI":"10.1186\/s13024-020-00409-0"},{"key":"ref86","doi-asserted-by":"crossref","unstructured":"Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. a meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. Journal of the American Medical Association. 1997; 278: 1349\u20131356.","DOI":"10.1001\/jama.278.16.1349"},{"key":"ref87","doi-asserted-by":"crossref","unstructured":"Crean S, Ward A, Mercaldi CJ, Collins JM, Cook MN, Baker NL, et al. Apolipoprotein E \u03b54 prevalence in Alzheimer\u2019s disease patients varies across global populations: a systematic literature review and meta-analysis. Dementia and Geriatric Cognitive Disorders. 2011; 31: 20\u201330.","DOI":"10.1159\/000321984"},{"key":"ref88","doi-asserted-by":"crossref","unstructured":"Fan K, Feingold E, Rosenthal SL, Demirci FY, Ganguli M, Lopez OL, et al. Whole-Exome Sequencing Analysis of Alzheimer\u2019s Disease in Non-APOE*4 Carriers. Journal of Alzheimer\u2019s Disease. 2020; 76: 1553\u20131565.","DOI":"10.3233\/JAD-200037"},{"key":"ref89","doi-asserted-by":"crossref","unstructured":"Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, et al. Human apoE isoforms differentially regulate brain amyloid-\u03b2 peptide clearance. Science Translational Medicine. 2011; 3: 89ra57.","DOI":"10.1126\/scitranslmed.3002156"},{"key":"ref90","doi-asserted-by":"crossref","unstructured":"Mahoney-Sanchez L, Belaidi AA, Bush AI, Ayton S. The Complex Role of Apolipoprotein E in Alzheimer\u2019s Disease: an Overview and Update. Journal of Molecular Neuroscience. 2016; 60: 325\u2013335.","DOI":"10.1007\/s12031-016-0839-z"},{"key":"ref91","doi-asserted-by":"crossref","unstructured":"Love S, Siew LK, Dawbarn D, Wilcock GK, Ben-Shlomo Y, Allen SJ. Premorbid effects of APOE on synaptic proteins in human temporal neocortex. Neurobiology of Aging. 2006; 27: 797\u2013803.","DOI":"10.1016\/j.neurobiolaging.2005.04.008"},{"key":"ref92","doi-asserted-by":"crossref","unstructured":"Cosentino S, Scarmeas N, Helzner E, Glymour MM, Brandt J, Albert M, et al. APOE epsilon 4 allele predicts faster cognitive decline in mild Alzheimer disease. Neurology. 2008; 70: 1842\u20131849.","DOI":"10.1212\/01.wnl.0000304038.37421.cc"},{"key":"ref93","doi-asserted-by":"crossref","unstructured":"Agosta F, Vossel KA, Miller BL, Migliaccio R, Bonasera SJ, Filippi M, et al. Apolipoprotein E epsilon4 is associated with disease-specific effects on brain atrophy in Alzheimer\u2019s disease and frontotemporal dementia. Proceedings of the National Academy of Sciences of the United States of America. 2009; 106: 2018\u20132022.","DOI":"10.1073\/pnas.0812697106"},{"key":"ref94","doi-asserted-by":"crossref","unstructured":"Wolfe CM, Fitz NF, Nam KN, Lefterov I, Koldamova R. The Role of APOE and TREM2 in Alzheimer\u2019s Disease-Current Understanding and Perspectives. International Journal of Molecular Sciences. 2018; 20: 81.","DOI":"10.3390\/ijms20010081"}],"container-title":["Journal of Integrative Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/JIN\/21\/4\/10.31083\/j.jin2104105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T15:38:58Z","timestamp":1732721938000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/JIN\/21\/4\/10.31083\/j.jin2104105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,1]]},"references-count":94,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022]]}},"alternative-id":["S0219-6352(22)00384-9"],"URL":"https:\/\/doi.org\/10.31083\/j.jin2104105","relation":{},"ISSN":["0219-6352","1757-448X"],"issn-type":[{"value":"0219-6352","type":"print"},{"value":"1757-448X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,1]]},"article-number":"105"}}