The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk
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Abstract
Common variants in the microglia-specific MS4A gene cluster modify risk for late-onset Alzheimer’s disease and modulate extracellular soluble TREM2.
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TREM2 function is regulated via interactions and crosstalk with other receptors, including the AD risk hits CD33, and the Ms4A gene-cluster products.
“TREM2 function is regulated via interactions and crosstalk with other receptors, including the AD risk hits CD33, and the Ms4A gene-cluster products [23, 59].”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [59]
The Results report that MS4A4A and TREM2 colocalize in human macrophages, and the Discussion reports that changing MS4A4A expression or targeting it with antibodies changes extracellular soluble TREM2. This supports crosstalk with an MS4A gene-cluster product, but the paper does not establish a direct interaction or regulation of TREM2 receptor function. The cited passages do not address CD33. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMyelin dysfunction does not affect TREM2 protein levels or cleavage through increased Ms4a expression.
“As Ms4a genes can regulate the level of soluble TREM2 and modify AD risk39, we used immunoblot analysis to rule out the possibility that myelin dysfunction affects TREM2 protein levels or cleavage through increased Ms4a expression (Extended Data Fig. 9a).”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [39]
Targeting CSF proteins has proven successful at elucidating causal genes at some disease GWAS loci.
“Targeting CSF proteins has proven successful at elucidating causal genes at some disease GWAS loci, including an association for the TREM2 protein at the MS4A locus potentially an Alzheimer’s Disease (AD) risk locus7,20 and an association for GRN protein levels near LRRK2 potentially relevant for Parkinson’s Disease (PD)21.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [7]
The enrichment of prioritized proteins in microglia and immune pathways supports a strong immunological role in AD, including TREM2, CD33, and IL34.
“supporting a strong immunological role in AD93–95 including TREM27,96, CD33, and IL34.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [7]
MS4A6A showed a region-specific effect of age.
“MS4A6A, a gene related to AD risk22,68,69, was one of the genes that showed a region-specific effect of age68,70.”
From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [69]
The Results section on functional annotation reports tissue-specific effects of rs1582763 on MS4A6A expression, but does not examine whether age affects MS4A6A differently across regions. The Discussion mentions age at Alzheimer’s disease onset, which is a different outcome. Searches for a region-specific effect of age and age-dependent MS4A6A expression found no supporting passage in our copy; page numbers were unavailable. (LLM, conf=0.77)
Experimental — accuracy not yet measured
Common variants in the MS4A gene cluster were shown to significantly regulate sTREM2 levels in CSF.
“Common variants in the MS4A gene cluster were shown to significantly regulate sTREM2 levels in CSF [134], demonstrating regulation of this endophenotype is orchestrated by genetic variants that also modify risk for disease.”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [134]
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TREM2-Ligand Interactions in Health and Disease
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“Some evidence suggests that sTREM2 binds to and sequesters TREM2 ligands, such as apolipoproteins, thus preventing these ligands from activating the TREM2 receptor (53, 54).”
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 · cited 3× · see citing works
“In this study, we did not analyze the association of sTREM2 with AD clinical status because previous studies (24, 25) have recently demonstrated that sTREM2 is associated with AD risk.”
Self-citationSchlepckow, K., Kleinberger, G., Fukumori, A., Feederle, R., Lichtenthaler, S. F., Steiner, H., & Haass, C. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201707672 · Cited by 258 · cited 2× · see citing works
“Recently, a cleavage site was identified in TREM2, which can be targeted by proteases such as ADAM10, ADAM17, and -secretase to generate sTREM2 (21, 22).”
Self-citationImpaired Differentiation of Osteoclasts in TREM-2–deficient Individuals
Cella, M., Buonsanti, C., Strader, C., Kondo, T., Salmaggi, A., & Colonna, M. (2003) · Journal of Experimental Medicine · doi:10.1084/jem.20022220 · Cited by 256 · cited 2× · see citing works
“S9, E, F and H), which is consistent with previous reports (41, 42).”
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 · cited 1× · see citing works
“Our findings and previous studies indicate that increasing TREM2 or activating the TREM2 signaling pathway could offer a new therapeutic approach for treating AD (45).”
(ADNI), A. D. N. I., Deming, Y., The Alzheimer Disease Genetic Consortium (ADGC), Li, Z., Kapoor, M., Harari, O., Del-Aguila, J. L., Black, K., Carrell, D., Cai, Y., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1685-y · Cited by 231 · see citing works
Self-citationTrabzuni, D., Ryten, M., Walker, R., Smith, C., Imran, S., Ramasamy, A., Weale, M. E., & Hardy, J. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07432.x · Cited by 229 · cited 9× · see citing works
“Similarly, rs1582763 produced a nominal cis-eQTL effect on MS4A6A expression in GTEx (frontal cortex: = 0.183, P = 0.04; cortex: = 0.165, P = 0.05) and Braineac (medulla: = 0.337, P = 4.50 × 10 −4 ) human brain tissue samples.”
InfluentialTREM2 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
Yuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.09.016 · Cited by 219 · see citing works
Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease
Cruchaga, C., Kauwe, J. S. K., Nowotny, P., Bales, K., Pickering, E. H., Mayo, K., Bertelsen, S., Hinrichs, A., Fagan, A. M., Holtzman, D. M., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds296 · Cited by 207 · see citing works
Self-citationThornton, P., Sevalle, J., Deery, M. J., Fraser, G., Zhou, Y., Ståhl, S., Franssen, E. H., Dodd, R. B., Qamar, S., Gomez Perez‐Nievas, B., et al. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201707673 · Cited by 200 · cited 2× · see citing works
“Recently, a cleavage site was identified in TREM2, which can be targeted by proteases such as ADAM10, ADAM17, and -secretase to generate sTREM2 (21, 22).”
TREM2 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 · cited 1× · see citing works
“Some evidence suggests that sTREM2 binds to and sequesters TREM2 ligands, such as apolipoproteins, thus preventing these ligands from activating the TREM2 receptor (53, 54).”
Variants in TF and HFE Explain ∼40% of Genetic Variation in Serum-Transferrin Levels
Benyamin, B., McRae, A. F., Zhu, G., Gordon, S. D., Henders, A. K., Palotie, A. V., Peltonen, L., Martin, N. G., Montgomery, G. W., Whitfield, J. B., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.11.011 · Cited by 169 · 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
Self-citationGuerreiro, 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 · cited 1× · see citing works
“R47H is also associated with clinical, imaging, and neuropathological AD phenotypes, including advanced behavioral symptoms, gray matter atrophy, and Braak staging (3, 4).”
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
Self-citationCerebrospinal 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 · cited 1× · see citing works
“Recently, a cleavage site was identified in TREM2, which can be targeted by proteases such as ADAM10, ADAM17, and -secretase to generate sTREM2 ( 21 , 22 ). sTREM2 is released into the cerebrospinal fluid (CSF) where it can be quantified ( 13 , 23 – 28 ).”
Cruchaga, C., Kauwe, J. S. K., Mayo, K., Spiegel, N., Bertelsen, S., Nowotny, P., Shah, A. R., Abraham, R., Hollingworth, P., Harold, D., et al. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001101 · Cited by 128 · see citing works
Self-citationAlzheimer’s disease risk polymorphisms regulate gene expression in the ZCWPW1 and the CELF1 loci
Karch, C. M., Ezerskiy, L. A., Bertelsen, S., Alzheimer’s Disease Genetics Consortium (ADGC), & Goate, A. M. (2016) · PLoS ONE · doi:10.1371/journal.pone.0148717 · Cited by 111 · see citing works
Self-citationLautner, R., Palmqvist, S., Mattsson, N., Andréasson, U., Wallin, A., Pålsson, E., Jakobsson, J., Herukka, S., Owenius, R., Olsson, B., et al. (2014) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2014.1060 · Cited by 107 · cited 1× · see citing works
“The influence of APOE genotype on A pathology, including CSF A42 concentration, has been a consistent finding (31, 35).”
Self-citationMS4A4A: a novel cell surface marker for M2 macrophages and plasma cells
Sanyal, R., Polyak, M. J., Zuccolo, J., Puri, M., Deng, L., Roberts, L., Zuba, A., Storek, J., Luider, J. M., Sundberg, E. M., et al. (2017) · Immunology and Cell Biology · doi:10.1038/icb.2017.18 · Cited by 99 · cited 6× · see citing works
“TREM2 and MS4A4A are both highly and specifically expressed in human microglia ( 38 ).”
InfluentialChang, T., & Chen, J. (2016) · Cardiovascular Diabetology · doi:10.1186/s12933-016-0439-9 · Cited by 87 · see citing works
Johansson, P., Mattsson, N., Hansson, O., Wallin, A., Johansson, J.-O., Andréasson, U., Zetterberg, H., Blennow, K., & Svensson, J. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101878 · Cited by 71 · cited 1× · see citing works
“We also evaluated whether CSF sTREM2 was associated with sex, as previously reported ( 24 – 26 , 32 ).”
Self-citationThe Dominantly Inherited Alzheimer Network (DIAN), Li, Z., Del-Aguila, J. L., Dube, U., Budde, J., Martinez, R., Black, K., Xiao, Q., Cairns, N. J., Dougherty, J. D., et al. (2018) · Genome Medicine · doi:10.1186/s13073-018-0551-4 · Cited by 56 · see citing works
Self-citationDeming, Y. K., Li, Z., Benítez, B. A., & Cruchaga, C. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2018.1486823 · Cited by 48 · cited 1× · see citing works
“Recent evidence from AD animal models suggests that TREM2 has a complex relationship with the key proteins involved in AD pathogenesis, amyloid- (A ) and tau ( 12 ).”
Self-citationRarity of the Alzheimer Disease–ProtectiveAPPA673T Variant in the United States
Wang, L.-S., Naj, A. C., Graham, R., Crane, P. K., Kunkle, B. W., Cruchaga, C., Murcia, J. D. G., Cannon‐Albright, L., Baldwin, C. T., Zetterberg, H., et al. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.2157 · Cited by 47 · see citing works
Self-citationFrontobasal gray matter loss is associated with the TREM2 p.R47H variant
Luis, E. O., Ortega-Cubero, S., Lamet, I., Razquin, C., Cruchaga, C., Benitez, B. A., Lorenzo, E., Irigoyen, J., Pastor, M. A., & Pastor, P. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.06.007 · Cited by 47 · see citing works
Self-citationKauwe, J. S. K., Cruchaga, C., Bertelsen, S. E., Mayo, K., Latu, W., Nowotny, P., Hinrichs, A. L., Fagan, A. M., Holtzman, D. M., Initiative, A. D. N., et al. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-091711 · Cited by 43 · see citing works
Self-citationCui, L., Gao, Y., Xie, Y., Wang, Y., Cai, Y., Shao, X., Ma, X., Li, Y., Ma, G., Liu, G., et al. (2015) · Critical Care · doi:10.1186/s13054-015-0796-x · Cited by 42 · cited 1× · see citing works
“However, the risk variants in TYROBP are all rare (59, 60), and although there are variants in ADAM10 known to affect the function or expression of ADAM10, these variants also occur infrequently (61).”
Cruse, G., Beaven, M. A., Music, S. C., Bradding, P. H., Gilfillan, A. M., & Metcalfe, D. D. (2015) · Molecular Biology of the Cell · doi:10.1091/mbc.e14-07-1221 · Cited by 41 · cited 2× · see citing works
“Whereas the function of MS4A4A in the brain is poorly understood, it may be involved in protein trafficking and clathrin-dependent endocytosis (44).”
Garge, N., Pan, H., Rowland, M. D., Cargile, B. J., Zhang, X., Cooley, P. C., Page, G. P., & Bunger, M. K. (2010) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m900378-mcp200 · Cited by 36 · see citing works
Rodgers, K. M., Deming, Y. K., Bercum, F. M., Chumachenko, S. Y., Wieseler, J. L., Johnson, K. W., Watkins, L. R., & Barth, D. S. (2013) · Journal of Neurotrauma · doi:10.1089/neu.2013.3090 · Cited by 33 · see citing works
Self-citationGenetic studies of plasma analytes identify novel potential biomarkers for several complex traits
Deming, Y., Xia, J., Cai, Y., Lord, J., Del-Aguila, J. L., Fernandez, M. V., Carrell, D., Black, K., Budde, J., Ma, S., et al. (2016) · Scientific Reports · doi:10.1038/srep18092 · Cited by 28 · see citing works
Self-citationBenítez, B. A., & Sands, M. S. (2017) · Scientific Reports · doi:10.1038/s41598-017-06710-1 · Cited by 23 · cited 2× · see citing works
“Lentivirus vector preparation and experiments Lentiviral vectors encoding human MS4A4A WT cDNA (NM_148975) Myc-DDK-tagged (RC204646L1), GFP (PS100071), the shRNA for MS4A4A (pGFP-C-shLenti MS4A4A (TL303135B), and the control shRNA pGFP-C-shLenti Scrambled (TR30021) were obtained from OriGene and produced as previously…”
Li, Z., Del‐Aguila, J. L., Dube, U., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/266296 · Cited by 3 · see citing works
Self-citationPanoutsopoulou, K., Thiagarajah, S., Day-Williams, A., Southam, L., Hatzikotoulas, K., Matchan, A., Doherty, M., Wilkinson, J. M., & Zeggini, E. (2014) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2014.02.447 · Cited by 1 · see citing works
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Scheltens, P., De Strooper, B., Kivipelto, M., Holstege, H., Chételat, G., Teunissen, C. E., Cummings, J., & van der Flier, W. M. (2021) · The Lancet · doi:10.1016/s0140-6736(20)32205-4 · Cited by 5,465 · see citing works
Large-scale integration of the plasma proteome with genetics and disease
Ferkingstad, E., Sulem, P., Atlason, B. A., Sveinbjornsson, G., Magnusson, M. I., Styrmisdottir, E. L., Gunnarsdottir, K., Helgason, A., Oddsson, A., Halldorsson, B. V., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00978-w · Cited by 1,697 · see citing works
The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway
Deczkowska, A., Weiner, A., & Amit, I. (2020) · Cell · doi:10.1016/j.cell.2020.05.003 · Cited by 648 · see citing works
Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease
Depp, C., Sun, T., Sasmita, A. O., Spieth, L., Berghoff, S. A., Nazarenko, T., Overhoff, K., Steixner-Kumar, A. A., Subramanian, S., Arinrad, S., et al. (2023) · Nature · doi:10.1038/s41586-023-06120-6 · Cited by 476 · see citing works
Self-citationMeningeal lymphatics affect microglia responses and anti-Aβ immunotherapy
Da Mesquita, S., Papadopoulos, Z., Dykstra, T., Brase, L., Farias, F. G., Wall, M., Jiang, H., Kodira, C. D., de Lima, K. A., Herz, J., et al. (2021) · Nature · doi:10.1038/s41586-021-03489-0 · Cited by 431 · see citing works
Self-citationAlzheimer’s disease: insights into pathology, molecular mechanisms, and therapy
Zheng, Q., & Wang, X. (2024) · Protein & Cell · doi:10.1093/procel/pwae026 · Cited by 454 · see citing works
Colonna, M. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00837-1 · Cited by 394 · see citing works
TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease
Yang, J., Wise, L., & Fukuchi, K.-I. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00724 · Cited by 387 · see citing works
“MS4A6A) Maybe (63) No Maybe (63) Ligand binding promotes calcium conductance; may modulate TREM2 expression (and TLR/complement through TREM2) (63) TLR4 variant (rs4986790) Yes Yes No Altered ability to recruit MyD88 and TRIF (64) TREM2 Yes (65, 66) Maybe (67) Yes (68, 69) Found on myeloid cells and alters inflammator…”
BackgroundThe neuroimmune axis of Alzheimer’s disease
Jorfi, M., Maaser‐Hecker, A., & Tanzi, R. E. (2023) · Genome Medicine · doi:10.1186/s13073-023-01155-w · Cited by 299 · see citing works
“…TSPAN14 Mast cell function Orinska et al., 2020 [82] 11 MS4A Expressed in immune cells, TREM2 regulation, phagocytosis, regulation of complement system Deming et al., 2019 [83]; Kuek et al., 2016 [84] 11 PICALM Endocytosis and Aβ clearance Zhao et al., 2015 [72]; Harold et al., 2009 [85] 11…”
BackgroundYang, C., Farias, F. H. G., Ibanez, L., Suhy, A., Sadler, B., Fernandez, M. V., Wang, F., Bradley, J. L., Eiffert, B., Bahena, J. A., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00886-6 · Cited by 290 · see citing works
Self-citationMicroglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials
Miao, J., Ma, H., Yang, Y., Liao, Y., Lin, C., Zheng, J., Yu, M., & Lan, J. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1201982 · Cited by 293 · see citing works
“MS4A (Deming et al., 2019) rs983392 Four-pass transmembrane protein in MS4A family Microglial receptor complex”
BackgroundRestoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease
Jia, L., Piña-Crespo, J., & Li, Y. (2019) · Molecular Brain · doi:10.1186/s13041-019-0525-5 · Cited by 288 · see citing works
Lopes, K. D. P., Snijders, G. J. L., Humphrey, J., Allan, A., Sneeboer, M. A. M., Navarro, E., Schilder, B. M., Vialle, R. A., Parks, M., Missall, R., et al. (2022) · Nature Genetics · doi:10.1038/s41588-021-00976-y · Cited by 273 · see citing works
APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer’s disease
Nguyen, A. T., Wang, K., Hu, G., Wang, X., Miao, Z., Azevedo, J. A., Suh, E., Van Deerlin, V. M., Choi, D., Roeder, K., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02200-3 · Cited by 241 · see citing works
Impact of TREM2R47H variant on tau pathology–induced gliosis and neurodegeneration
Gratuze, M., Leyns, C. E. G., Sauerbeck, A. D., St-Pierre, M.-K., Xiong, M., Kim, N., Serrano, J. R., Tremblay, M.-È., Kummer, T. T., Colonna, M., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci138179 · Cited by 252 · see citing works
Microglia in Alzheimer's Disease: Exploring How Genetics and Phenotype Influence Risk
McQuade, A., & Blurton-Jones, M. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.01.045 · Cited by 244 · see citing works
Advancing cell therapy for neurodegenerative diseases
Temple, S. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.03.017 · Cited by 206 · see citing works
TREM2 dependent and independent functions of microglia in Alzheimer’s disease
Hou, J., Chen, Y., Grajales-Reyes, G., & Colonna, M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00588-y · Cited by 191 · see citing works
Morenas‐Rodríguez, E., Li, Y., Nuscher, B., Franzmeier, N., Xiong, C., Suárez‐Calvet, M., Fagan, A. M., Schultz, S., Gordon, B. A., Benzinger, T. L. S., et al. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(22)00027-8 · Cited by 177 · see citing works
“No modifying effect was noted by sex, level of education, age, or EYO at baseline on the subsequent rate of change in soluble TREM2 in carriers of pathogenic variants and non-carriers (appendix p 11).”
InfluentialSelf-citationZhong, L., Sheng, X., Wang, W., Li, Y., Zhuo, R., Wang, K., Zhang, L., Hu, D.-D., Hong, Y., Chen, L., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.06.016 · Cited by 168 · see citing works
A global view of the genetic basis of Alzheimer disease
Reitz, C., Pericak-Vance, M., Foroud, T., & Mayeux, R. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00789-z · Cited by 143 · see citing works
Wang, P. L., Yim, A. K., Kim, K.-W., Avey, D. R., Czepielewski, R. S., Colonna, M., Milbrandt, J., Randolph, G. J., & The Immunological Genome Project (2020) · Nature Communications · doi:10.1038/s41467-020-16355-w · Cited by 168 · see citing works
Walker, K. A., Chen, J., Shi, L., Yang, Y., Fornage, M., Zhou, L., Schlosser, P., Surapaneni, A., Grams, M. E., Duggan, M. R., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adf5681 · Cited by 148 · see citing works
Ewers, M., Biechele, G., Suárez‐Calvet, M., Sacher, C., Blume, T., Morenas‐Rodriguez, E., Deming, Y., Piccio, L., Cruchaga, C., Kleinberger, G., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.202012308 · Cited by 133 · see citing works
“Furthermore, a common genetic variant in the 4-domain subfamily gene MS4A4A that is associated with decreased risk of AD was found to be associated with higher CSF sTREM2 levels (Deming et al, 2019), suggesting that higher sTREM2 levels may contribute to a decreased risk of AD.”
BackgroundSelf-citationSoluble 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
Self-citationMicroglia in Alzheimer’s Disease: A Target for Therapeutic Intervention
Zhang, G., Wang, Z., Hu, H., Zhao, M., & Sun, L. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.749587 · Cited by 132 · see citing works
“MS4A modulates soluble TREM2 production and interacts with APOE, which appears to be an important modulator in AD pathogenesis (Ma et al., 2015; Chang et al., 2019; Deming et al., 2019).”
BackgroundGenetic architecture of Alzheimer's disease
Neuner, S. M., TCW, J., & Goate, A. M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104976 · Cited by 126 · see citing works
“Common variants in the MS4A gene cluster were shown to significantly regulate sTREM2 levels in CSF (Deming et al., 2019), demonstrating regulation of this endophenotype is orchestrated by genetic variants that also modify risk for disease.”
BackgroundInfluentialProtective genes and pathways in Alzheimer’s disease: moving towards precision interventions
Seto, M., Weiner, R. L., Dumitrescu, L., & Hohman, T. J. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00452-5 · Cited by 135 · see citing works
The role of innate immunity in Alzheimer's disease
Ennerfelt, H. E., & Lukens, J. R. (2020) · Immunological Reviews · doi:10.1111/imr.12896 · Cited by 121 · see citing works
Schlepckow, K., Morenas‐Rodríguez, E., Hong, S. Y., & Haass, C. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(23)00247-8 · Cited by 121 · see citing works
Self-citationMicroglial efferocytosis: Diving into the Alzheimer’s disease gene pool
Romero-Molina, C., Garretti, F., Andrews, S. J., Marcora, E., & Goate, A. M. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.015 · Cited by 111 · see citing works
Western, D., Timsina, J., Wang, L., Wang, C., Yang, C., Phillips, B., Wang, Y., Liu, M., Ali, M., Beric, A., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01972-8 · Cited by 111 · see citing works
Self-citationTREM2 brain transcript-specific studies in AD and TREM2 mutation carriers
Del‐Aguila, J. L., Benítez, B. A., Li, Z., Dube, U., Mihindukulasuriya, K. A., Budde, J., Farias, F., Fernández, M. V., Ibáñez, L., Jiang, S., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0319-3 · Cited by 103 · see citing works
“In any case, recent studies indicate that minor changes in sTREM2 levels, of around 7–10% are enough to modulate AD risk [54, 65].”
BackgroundSelf-citationLipid rafts in glial cells: role in neuroinflammation and pain processing
Miller, Y. I., Pelaez, J. M. N., Corr, M., & Yaksh, T. L. (2019) · Journal of Lipid Research · doi:10.1194/jlr.tr119000468 · Cited by 108 · see citing works
“calizes in lipid rafts with DAP12 (62) and also with membrane-spanning 4-domains subfamily A (MS4A), which modulates the production of soluble TREM2 (63).”
BackgroundInfluentialLi, Z., Farias, F. H. G., Dube, U., Del-Aguila, J. L., Mihindukulasuriya, K. A., Fernandez, M. V., Ibanez, L., Budde, J. P., Wang, F., Lake, A. M., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-019-02066-0 · Cited by 85 · see citing works
Self-citationThe tetraspan MS4A family in homeostasis, immunity, and disease
Mattiola, I., Mantovani, A., & Locati, M. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.07.002 · Cited by 101 · see citing works
Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
Brase, L., You, S., Albanus, R. D., Del‐Aguila, J. L., Dai, Y., Novotny, B. C., Soriano‐Tárraga, C., Dykstra, T., Fernández, M. V., Budde, J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37437-5 · Cited by 88 · see citing works
Self-citationPlasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults
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“All SNPs in the 99% credible sets were annotated with VEP (http:// grch37.ensembl.org/Homo_sapiens/Tools/VEP) using default criteria to select one block of annotation per variant (Table S4).”
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“Some studies investigating the role of the MS4A family suggest mechanisms that involve immune function, particularly among microglia 79 .”
Timing of Biomarker Changes in Sporadic Alzheimer's Disease in Estimated Years from Symptom Onset
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Functional insights from biophysical study of TREM2 interactions with apoE and Aβ 1‐42
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“Additionally, a common variant in the membrane-spanning 4-domains subfamily A ( MS4A ) gene, specifically MS4A4A, has been linked to increased CSF sTREM2 concentrations and a reduced risk of AD [37].”
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Self-citationThe Links between Cardiovascular Diseases and Alzheimer's Disease
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“Different variants of CR1 gene, which encodes the complement component (3b/4b) receptor 1, have been shown to relate to SAD development [85, 104, 109, 117] as well as BIN1 [85, 93, 104, 109, 118], CD33 [85, 104, 112], MS4A6A/MS4A4E [85, 104, 112, 119], TREM2 [85, 120], etc.”
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“MS4A7 belongs to a family of membrane proteins that contain four transmembrane domains and are expressed in diverse immune cell types ( 29 – 31 ).”
BackgroundTREM2 and sTREM2 in Alzheimer’s disease: from mechanisms to therapies
Zhang, L., Xiang, X., Li, Y., Bu, G., & Chen, X. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00834-z · Cited by 78 · see citing works
“Variants such as rs1582763 in the MS4A region are associated with increased CSF sTREM2 levels, reduced AD risk, and delayed disease onset [121].”
Neuroimmune contributions to Alzheimer’s disease: a focus on human data
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Self-citationMicroglia, Trem2, and Neurodegeneration
Shi, Q., Gutierrez, R. A., & Bhat, M. A. (2025) · The Neuroscientist · doi:10.1177/10738584241254118 · Cited by 69 · see citing works
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“TREM2 function is regulated via interactions and crosstalk with other receptors, including the AD risk hits CD33, and the Ms4A gene-cluster products [23, 59].”
BackgroundSingle-cell multiplex chromatin and RNA interactions in ageing human brain
Wen, X., Luo, Z., Zhao, W., Calandrelli, R., Nguyen, T. C., Wan, X., Richard, J. L. C., & Zhong, S. (2024) · Nature · doi:10.1038/s41586-024-07239-w · Cited by 67 · see citing works
“7m–o), which may reflect microglial sub-populations in the chemokine state relative to the interferon state 37 .”
Secretases in Alzheimer's disease: Novel insights into proteolysis of APP and TREM2
Lichtenthaler, S. F., Tschirner, S. K., & Steiner, H. (2022) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2021.09.003 · Cited by 60 · see citing works
Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease
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Cell type-specific changes identified by single-cell transcriptomics in Alzheimer’s disease
Luquez, T., Gaur, P., Kosater, I. M., Lam, M., Lee, D. I., Mares, J. A., Paryani, F., Yadav, A., & Menon, V. (2022) · Genome Medicine · doi:10.1186/s13073-022-01136-5 · Cited by 59 · see citing works
“identified that carriers of the MS4A rs1582763 variant, which is associated with reduced AD risk and delayed age of disease onset [53], have higher proportions of a microglial subcluster upregulating pro-inflammatory genes including IL1B, FCGR3A, C3, NPC1, PAG1, and CD40.”
BackgroundEbright, B., Assante, I., Poblete, R. A., Wang, S., Duro, M. V., Bennett, D. A., Arvanitakis, Z., Louie, S. G., & Yassine, H. N. (2022) · Alzheimer's Research & Therapy · doi:10.1186/s13195-022-01084-7 · Cited by 56 · see citing works
Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease
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Cognitively healthy centenarians are genetically protected against Alzheimer's disease
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“Comparison of cohorts used by our previous (Deming et al 2019) and our current paper.”
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“One potential mechanism is that ligated TREM2-DAP12 complexes may segregate to “lipid rafts” in the plasma membrane [65, 66], whereas ADAM10 is thought to be excluded from lipid rafts [67].”
BackgroundCoding and regulatory variants are associated with serum protein levels and disease
Emilsson, V., Guðmundsdóttir, V., Guðjónsson, A., Jónmundsson, Þ., Jonsson, B. G., Karim, M. A., Ilkov, M., Staley, J. R., Gudmundsson, E. F., Launer, L. J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28081-6 · Cited by 54 · see citing works
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“…and C2 were characterized by canonical immune-inhibitory genes such as Apoe, Tgfb1, Fcgr2b, Trem2, Axl and S100a4 71 , while cluster C1 was additionally featured with M2-associated scavenger Msr1 72 , TREM2-associated CD20-like family Ms4a4c 73 , immunosuppression-related Fgl2 74 , and Arg1 (Fig.”
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African Americans Have Differences in CSF Soluble TREM2 and Associated Genetic Variants
Schindler, S. E., Cruchaga, C., Joseph, A., McCue, L. M., Farias, F., Wilkins, C. H., Deming, Y. K., Henson, R. L., Mikesell, R. J., Piccio, L. M., et al. (2021) · Neurology Genetics · doi:10.1212/nxg.0000000000000571 · Cited by 49 · see citing works
Self-citationThe role of TREM2 in Alzheimer’s disease: from the perspective of Tau
Huang, W., Huang, J., Huang, N., & Luo, Y. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1280257 · Cited by 49 · see citing works
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“The modulation effects by MS4A4A indicated that TREM2 is participated in sporadic AD pathogenesis, not only in TREM2 risk-variant carriers [200].”
BackgroundTimsina, J., Ali, M., Do, A. N., Wang, L., Western, D., Sung, Y. J., & Cruchaga, C. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106373 · Cited by 47 · see citing works
“Similarly, by using CSF sTREM2 as endophenotype, Deming et al. (2019) were able to demonstrate the role of MS4A gene cluster in AD mechanism.”
BackgroundMethodSelf-citationArnoriaga‐Rodríguez, M., Mayneris‐Perxachs, J., Contreras‐Rodríguez, O., Burokas, A., Ortega-Sanchez, J.-A., Blasco, G., Coll, C., Biarnés, C., Castells‐Nobau, A., Puig, J., et al. (2021) · Gut · doi:10.1136/gutjnl-2020-323371 · Cited by 48 · see citing works
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“In particular, several neurotoxic damage-associated microglia-specific transcriptomic signatures have been identified in mice as well as a human-specific microglial signature observed in AD patients and in normal aging [50, 72, 228, 229].”
BackgroundPanyard, D. J., McKetney, J., Deming, Y. K., Morrow, A. R., Ennis, G. E., Jonaitis, E. M., Hulle, C. A. V., Yang, C., Sung, Y. J., Ali, M., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13130 · Cited by 46 · see citing works
Self-citationNovel Targets for Alzheimer's Disease: A View Beyond Amyloid
Ray, W. J., & Buggia-Prévot, V. (2020) · Annual Review of Medicine · doi:10.1146/annurev-med-052919-120219 · Cited by 43 · see citing works
Does Soluble TREM2 Protect Against Alzheimer's Disease?
Brown, G. C., & George‐Hyslop, P. S. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.834697 · Cited by 43 · see citing works
Regulation of the Late Onset alzheimer’s Disease Associated HLA-DQA1/DRB1 Expression
Zhang, X., Zou, M., Wu, Y., Jiang, D., Wu, T., Zhao, Y., Wu, D., Cui, J., & Li, G. (2022) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/15333175221085066 · Cited by 45 · see citing works
“MS4A2 is a keymodulator of soluble TREM2, another LOAD risk gene.(43) CDH1, an activator subunit of APC/C (The anaphase promoting complex/cyclosome), is highly expressed in post-mitotic neurons(44) and its degradation induced by Aβ resulted in neuronal apoptosis.”
BackgroundHe, L., Loika, Y., Park, Y., Bennett, D. A., Kellis, M., Kulminski, A. M., & Initiative, A. D. N. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01263-4 · Cited by 40 · see citing works
“15 (0) 13 (3) 5 (10) 0 (14) 1 0 Number at risk (number of events) + + + + + + + + ++ + ++ +++++++++++++++++++++++++++ + +++++++++++++++++++ +++++++++++++++ ++++++”
Schaffner, S. L., & Kobor, M. S. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.971298 · Cited by 41 · see citing works
“variants associated with cerebrospinal fluid triggering receptor expressed on myeloid cells 2 (TREM2) levels, and tissue culture experiments were conducted to examine the functional implications of these variants (Deming et al., 2019).”
BackgroundAlbertini, G., Zielonka, M., Cuypers, M., Snellinx, A., Xu, C., Poovathingal, S. K., Wojno, M., Davie, K., van Lieshout, V., Craessaerts, K., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02125-8 · Cited by 47 · see citing works
Hou, X., Bi, Y., Tan, M., Xu, W., Li, J., Shen, X., Dou, K., Tan, C., Tan, L., & Yu, J. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.05.008 · Cited by 40 · see citing works
The Emerging Roles and Therapeutic Potential of Soluble TREM2 in Alzheimer’s Disease
Zhong, L., & Chen, X. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00328 · Cited by 40 · see citing works
Gao, C., Shen, X., Tan, Y., & Chen, S. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02580-1 · Cited by 43 · see citing works
“Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C, Rinker J 2nd, Naismith RT, Panina-Bordignon P, Passini N, et al. Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation.”
BackgroundInfluentialSynapses, Microglia, and Lipids in Alzheimer’s Disease
Paasila, P. J., Aramideh, J. A., Sutherland, G. T., & Graeber, M. B. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.778822 · Cited by 38 · see citing works
Yarbro, J. M., Shrestha, H. K., Wang, Z., Zhang, X., Zaman, M., Chu, M., Wang, X., Yu, G., & Peng, J. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00874-5 · Cited by 41 · see citing works
“For example, CSF pQTL analyses performed by Deming et al. showed that a genetic variant near MS4A6A and MS4A4A, associated with increased AD risk, was identified as a trans-pQTL that reduces soluble TREM2 levels in CSF [192].”
Ibáñez, L., Liu, M., Beric, A., Timsina, J., Kohlfeld, P., Bergmann, K., Lowery, J., Sykora, N., Montejo, B. S., Brock, W., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14413 · Cited by 40 · see citing works
Self-citationFernández, M. V., Liu, M., Beric, A., Johnson, M., Cetin, A., Patel, M. R., Budde, J., Kohlfeld, P., Bergmann, K., Lowery, J., et al. (2024) · Scientific Data · doi:10.1038/s41597-024-03485-9 · Cited by 41 · see citing works
Self-citationImmune modulation to treat Alzheimer’s disease
Duggan, M. R., Morgan, D., Price, B. R., Rajbanshi, B., Martín‐Peña, A., Tansey, M. G., & Walker, K. A. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00828-x · Cited by 39 · see citing works
The Ambiguous Role of Microglia in Aβ Toxicity: Chances for Therapeutic Intervention
Merlo, S., Spampinato, S. F., Caruso, G. I., & Sortino, M. A. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200131105418 · Cited by 35 · see citing works
Defining functional variants associated with Alzheimer’s disease in the induced immune response
Harwood, J. C., Leonenko, G., Sims, R., Escott‐Price, V., Williams, J. H., & Holmans, P. (2021) · Brain Communications · doi:10.1093/braincomms/fcab083 · Cited by 32 · see citing works
“have been reported as genome-wide significant and recently, both MS4A4A and MS4A6A have been shown to modulate TREM2, a component of a transmembrane receptor-signalling complex that is important in microglial activation and function.(52) The most significantly associated eQTL SNP in Fairfax CD14þ monocytes in our stud…”
CSF sTREM2 in neurological diseases: a two-sample Mendelian randomization study
Dong, M.-H., Zhou, L.-Q., Tang, Y., Chen, M., Xiao, J., Shang, K., Deng, G., Qin, C., & Tian, D.-S. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02443-9 · Cited by 31 · see citing works
“Available studies indicated that MS4A6A and TREM2 were both expressed mainly on microglia [42] and the MS4A gene region was associated with CSF sTREM2 levels [43], which suggested a biological relevance between MS4A6A gene and sTREM2.”
BackgroundGenome-Wide Association Studies for Cerebrospinal Fluid Soluble TREM2 in Alzheimer’s Disease
Liu, C., & Yu, J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00297 · Cited by 27 · see citing works
Chen, H., Eteleeb, A. M., Wang, C., Fernández, M. V., Budde, J., Bergmann, K., Norton, J. B., Wang, F., Ebl, C., Morris, J. C., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01328-5 · Cited by 31 · see citing works
Self-citationJagadeesh, K. A., Dey, K. K., Montoro, D. T., Mohan, R. R., Gazal, S., Engreitz, J., Xavier, R. J., Price, A. L., & Regev, A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.19.436212 · Cited by 31 · see citing works
“9 enrichment were MS4A6A and MS4A4A; the MS4A gene cluster is a modulator of TREM2, which plays a critical role in Alzheimer’s disease through monocyte-mediated microglial activation and phagocytosis(59).”
BackgroundMicroglia and its Genetics in Alzheimer's Disease
Liang, X., Wu, H., Colt, M., Guo, X., Pluimer, B. R., Zeng, J., Dong, S., & Zhao, Z. (2021) · Current Alzheimer Research · doi:10.2174/1567205018666211105140732 · Cited by 31 · see citing works
- Authors
- Deming, Y., Filipello, F., Cignarella, F., Cantoni, C., Hsu, S., Mikesell, R., Li, Z., Del-Aguila, J. L., Dube, U., Farias, F. G., Bradley, J., Budde, J., Ibanez, L., Fernandez, M. V., Blennow, K., Zetterberg, H., Heslegrave, A., Johansson, P. M., Svensson, J., Nellgård, B., Lleo, A., Alcolea, D., Clarimon, J., Rami, L., Molinuevo, J. L., Suárez-Calvet, M., Morenas-Rodríguez, E., Kleinberger, G., Ewers, M., Harari, O., Haass, C., Brett, T. J., Benitez, B. A., Karch, C. M., Piccio, L., & Cruchaga, C.
- Affiliations
- University of Wisconsin–Madison (US)
- Washington University in St. Louis (US)
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
- Lund University (SE)
- Sahlgrenska University Hospital (SE)
- Universitat Autònoma de Barcelona (ES)
- Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
- Pasqual Maragall Foundation (ES)
- Munich Cluster for Systems Neurology (DE)
- IDIBAPS, Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic, Barcelona, Spain.
- Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
- Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
- German Center for Neurodegenerative Diseases (DE)
- Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
- Corresponding author
- Deming, Yuetiva
- Filipello, Fabia
- Cignarella, Francesca
- Harari, Oscar
- Haass, Christian
- Karch, Celeste M.
- ORCID
- Deming, Yuetiva
- Filipello, Fabia
- Cignarella, Francesca
- Cantoni, Claudia
- Hsu, Simon
- Mikesell, Robert
- Li, Zeran
- Del-Aguila, Jorge L
- Dube, Umber
- Farias, Fabiana Geraldo
- Bradley, Joseph
- Budde, John
- Ibanez, Laura
- Fernandez, Maria Victoria
- Blennow, Kaj
- Zetterberg, Henrik
- Heslegrave, Amanda
- Johansson, Per M
- Svensson, Johan
- Nellgård, Bengt
- Alcolea, Daniel
- Clarimon, Jordi
- Rami, Lorena
- Suárez-Calvet, Marc
- Kleinberger, Gernot
- Ewers, Michael
- Harari, Oscar
- Haass, Christian
- Benitez, Bruno A.
- Karch, Celeste M.
- Piccio, Laura
- Cruchaga, Carlos
- Venue
- Science Translational Medicine
- Published
- 2019-08-14
- Volume
- 11
- Issue
- 505
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC6697053
- OpenAlex
- W2968181515
- Cited by
- 271
- References
- 90
- Citations by year
- 2026: 21 · 2025: 37 · 2024: 46 · 2023: 43 · 2022: 48 · 2021: 40 · 2020: 21 · 2019: 15
- FWCI
- 13.58
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Science Translational Medicine (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- National Institutes of Health (R01AG044546, P01AG003991, RF1AG053303, R01AG058501, R01AG035083)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- soluble TREM2, Alzheimer's disease risk, late-onset Alzheimer's disease, microglia, common genetic variants, genetic risk factors
- MeSH terms
- Alzheimer Disease, Female, Multigene Family, Humans, Macrophages, Male, Membrane Glycoproteins, Membrane Proteins, Receptors, Immunologic, Meta-Analysis as Topic, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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