The DOI matches its Crossref record; 91 of the 91 references it cites were found in a registry or an index.
The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk
Open accessPublished version of a preprint
Abstract
Common variants in the microglia-specific MS4A gene cluster modify risk for late-onset Alzheimer’s disease and modulate extracellular soluble TREM2.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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 cited source says what the claim attributes to it.
In the citing paper
“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]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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]
Experimental — accuracy not yet measured
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106 · cited 2×
“Gene counts data were transformed to stabilize expression variances along the range of mean values and normalized according to library size using the variance-stabilizing transformation (VST) function in DESeq2 (79).”
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709 · cited 1×
“2b (64), and reads alignment was further evaluated by applying Picard CollectRnaSeqMetrics v2.”
ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data
Wang, K., Li, M., & Hakonarson, H. H. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq603 · Cited by 14,611 · cited 1×
“Bioinformatics annotation All variants below the threshold for suggestive significance (P < 1 × 10−5) were taken forward for functional annotation using ANNOVAR version 2015-06-17 (81) and examined for potential regulatory functions using HaploReg v4.”
Second-generation PLINK: rising to the challenge of larger and richer datasets
Chang, C. C., Chow, C. C., Tellier, L. C., Vattikuti, S., Purcell, S. M., & Lee, J. J. (2015) · Gigascience · doi:10.1186/s13742-015-0047-8 · Cited by 12,709
Salmon provides fast and bias-aware quantification of transcript expression
Patro, R., Duggal, G., Love, M. I., Irizarry, R. A., & Kingsford, C. (2017) · Nature Methods · doi:10.1038/nmeth.4197 · Cited by 12,700 · cited 1×
“2 (78) transcript expression quantification of the coding transcripts of H.”
Principal components analysis corrects for stratification in genome-wide association studies
Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006) · Nature Genetics · doi:10.1038/ng1847 · Cited by 10,248 · cited 2×
“EIGENSTRAT ( 66 ) was used to calculate principal components.”
Near-optimal probabilistic RNA-seq quantification
Bray, N. L., Pimentel, H., Melsted, P., & Pachter, L. (2016) · Nature Biotechnology · doi:10.1038/nbt.3519 · Cited by 9,723 · cited 1×
“5 (65) was used to determine the read count for each transcript and quantified transcript abundance as transcripts per kilobase per million reads mapped (TPM), using gene annotation of Homo sapiens reference genome (GENCODE GRCh38) with the following parameter: -t 10 -b 100.”
The Ensembl Variant Effect Predictor
McLaren, W., Gil, L., Hunt, S. E., Riat, H. S., Ritchie, G. R. S., Thormann, A., Flicek, P., & Cunningham, F. (2016) · Genome Biology · doi:10.1186/s13059-016-0974-4 · Cited by 8,099 · cited 1×
“The Ensembl Variant Effect Predictor (VEP; http://grch37.ensembl.org/Homo_sapiens/ Tools/VEP) ( 86 ) was queried for the predicted effects of identified coding variants, including any applicable SIFT and PolyPhen scores.”
METAL: fast and efficient meta-analysis of genomewide association scans
Willer, C. J., Li, Y., & Abecasis, G. R. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq340 · Cited by 5,205 · cited 2×
“Meta-analyses were performed using a fixed effect model in METAL (77).”
The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans
The GTEx Consortium, Ardlie, K. G., Deluca, D. S., Segrè, A. V., Sullivan, T. J., Young, T. R., Gelfand, E. T., Trowbridge, C. A., Maller, J. B., Tukiainen, T., et al. (2015) · Science · doi:10.1126/science.1262110 · Cited by 5,062
Cited by
Sorted by citations
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
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
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
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 493
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
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 483
Colonna, M. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00837-1 · Cited by 394
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
“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 313
“…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
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
“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
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
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
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
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
Advancing cell therapy for neurodegenerative diseases
Temple, S. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.03.017 · Cited by 221
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
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 182
“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
A global view of the genetic basis of Alzheimer disease
Reitz, C., Pericak‐Vance, M. A., Foroud, T., & Mayeux, R. P. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00789-z · Cited by 171
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
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
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
“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
Self-citationProtective 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
Microglia 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 135
“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
“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.”
BackgroundInfluentialThe role of innate immunity in Alzheimer's disease
Ennerfelt, H. E., & Lukens, J. R. (2020) · Immunological Reviews · doi:10.1111/imr.12896 · Cited by 124
Schlepckow, K., Morenas‐Rodríguez, E., Hong, S. Y., & Haass, C. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(23)00247-8 · Cited by 122
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
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
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 106
“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., Navia-Pelaez, J. M., Corr, M., & Yaksh, T. L. (2020) · Journal of Lipid Research · doi:10.1194/jlr.tr119000468 · Cited by 112
“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
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
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 95
Self-citationPlasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults
Yang, H., Zhang, C., Carlyle, B. C., Zhen, S. Y., Trombetta, B. A., Schultz, A. P., Pruzin, J. J., Fitzpatrick, C. D., Yau, W. W., Kirn, D. R., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12399 · Cited by 90
Genomics of Alzheimer’s disease implicates the innate and adaptive immune systems
Li, Y., Laws, S. M., Miles, L. A., Wiley, J. S., Huang, X., Masters, C. L., & Gu, B. J. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03986-5 · Cited by 94
Multi-ancestry meta-analysis and fine-mapping in Alzheimer’s disease
Lake, J., Solsberg, C. W., Kim, J. J., Acosta‐Uribe, J., Makarious, M. B., Li, Z., Levine, K. S., Heutink, P., Alvarado, C. X., Vitale, D., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02089-w · Cited by 81
“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).”
MethodSelf-citationTang, A. S., Rankin, K. P., Cerono, G., Miramontes, S., Mills, H., Roger, J., Zeng, B., Nelson, C., Soman, K., Woldemariam, S., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00573-8 · Cited by 86
“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
Li, Y., Yen, D., Hendrix, R. D., Gordon, B. A., Dlamini, S. L., Barthélemy, N. R., Aschenbrenner, A. J., Henson, R. L., Herries, E. M., Volluz, K., et al. (2024) · Annals of Neurology · doi:10.1002/ana.26891 · Cited by 90
Friend, Foe or Both? Immune Activity in Alzheimer’s Disease
Frost, G. R., Jonas, L. A., & Li, Y. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00337 · Cited by 88
Apolipoprotein E4 and meningeal lymphatics in Alzheimer disease: a conceptual framework
Mentis, A. A., Dardiotis, E., & Chrousos, G. P. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0731-7 · Cited by 82
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
Lista, S., Imbimbo, B. P., Grasso, M., Fidilio, A., Emanuele, E., Minoretti, P., López-Ortiz, S., Martín-Hernández, J., Gabelle, A., Caruso, G., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03163-y · Cited by 81
“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].”
BackgroundFunctional insights from biophysical study of TREM2 interactions with apoE and Aβ 1‐42
Kober, D. L., Stuchell‐Brereton, M. D., Kluender, C. E., Dean, H. B., Strickland, M. R., Steinberg, D. F., Nelson, S. S., Baban, B. A., Holtzman, D. M., Frieden, C., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12194 · Cited by 85
Self-citationFilipello, F., You, S.-F., Mirfakhar, F. S., Mahali, S., Bollman, B., Acquarone, M., Korvatska, O., Marsh, J. A., Sivaraman, A., Martinez, R., et al. (2023) · Acta Neuropathologica · doi:10.1007/s00401-023-02568-y · Cited by 81
Self-citationLatest advances in cerebrospinal fluid and blood biomarkers of Alzheimer’s disease
Milà‐Alomà, M., Suárez‐Calvet, M., & Molinuevo, J. L. (2019) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756286419888819 · Cited by 81
Self-citationThe Links between Cardiovascular Diseases and Alzheimer's Disease
Leszek, J., Вячеславовна, М. Е., Belousov, D. M., Koutsouraki, E., Szczechowiak, K., Kobusiak−Prokopowicz, M., Mysiak, A., Diniz, B. S., Somasundaram, S. G., Kirkland, C. E., et al. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200729093724 · Cited by 93
“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.”
BackgroundInfluentialGenetic Markers of Alzheimer’s Disease
Perković, M. N., & Pivac, N. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9721-0_3 · Cited by 82
Zhou, L., Qiu, X., Meng, Z., Liu, T., Chen, Z., Zhang, P., Kuang, H., Pan, T., Lu, Y., Qi, L., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adk1866 · Cited by 85
“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 87
“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
Haage, V., & De Jager, P. L. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01637-0 · Cited by 74
Timsina, J., Gomez-Fonseca, D., Wang, L., Do, A., Western, D., Alvarez, I., Aguilar, M., Pastor, P., Henson, R. L., Herries, E., et al. (2022) · Journal of Alzheimer’s Disease · doi:10.3233/jad-220399 · Cited by 68
Self-citationMicroglia, Trem2, and Neurodegeneration
Shi, Q., Gutierrez, R. A., & Bhat, M. A. (2025) · The Neuroscientist · doi:10.1177/10738584241254118 · Cited by 69
Magno, L., Bunney, T. D., Mead, E., Svensson, F., & Bictash, M. N. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00436-5 · Cited by 64
“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 68
“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
Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease
Casali, B. T., & Reed-Geaghan, E. G. (2021) · Cells · doi:10.3390/cells10040957 · Cited by 70
Hall-Roberts, H., Agarwal, D., Obst, J., Smith, T. B., Monzón-Sandoval, J., Di Daniel, E., Webber, C., James, W. S., Mead, E., Davis, J. B., et al. (2020) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00709-z · Cited by 62
“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].”
BackgroundCell 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 64
“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
Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease
Ali, M., Archer, D. B., Gorijala, P., Western, D., Timsina, J., Fernández, M. V., Wang, T.-C., Satizabal, C. L., Yang, Q., Beiser, A. S., et al. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01563-4 · Cited by 54
Self-citationGan, Y., Ma, L., Zhang, Y., You, J., Guo, Y. X., He, Y., Wang, L., He, X.-Y., Li, Y., Dong, Q., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-00818-0 · Cited by 63
Cognitively healthy centenarians are genetically protected against Alzheimer's disease
Tesi, N., van der Lee, S., Hulsman, M., van Schoor, N. M., Huisman, M., Pijnenburg, Y., van der Flier, W. M., Reinders, M., & Holstege, H. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13810 · Cited by 52
Silva-Gomes, R., Mapelli, S. N., Boutet, M., Mattiola, I., Sironi, M., Grizzi, F., Colombo, F., Supino, D., Carnevale, S., Pasqualini, F., et al. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.2a0421-200r · Cited by 56
Yang, C., Fagan, A. M., Perrin, R. J., Rhinn, H., Harari, O., & Cruchaga, C. (2022) · Genome Medicine · doi:10.1186/s13073-022-01140-9 · Cited by 53
Self-citationWang, L., Nykänen, N.-P., Western, D., Gorijala, P., Timsina, J., Li, F., Wang, Z., Ali, M., Yang, C., Liu, M., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00687-4 · Cited by 58
“Comparison of cohorts used by our previous (Deming et al 2019) and our current paper.”
Self-citationCoding 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 59
Chen, S., Wang, Y., Dang, J., Song, N., Chen, X., Wang, J., Huang, G. N., Brown, C. E., Yu, J., Weissman, I. L., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59326-9 · Cited by 56
“…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.”
Pocock, J., Vasilopoulou, F., Svensson, E., & Cosker, K. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110020 · Cited by 54
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
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
Li, C., Ren, J., Zhang, M., Wang, H., Fang, Y., Wu, J., & Tang, Y. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04536-3 · Cited by 52
“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 48
“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
McFarland, K. N., & Chakrabarty, P. (2022) · Neurotherapeutics · doi:10.1007/s13311-021-01179-3 · Cited by 48
“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
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 46
Does soluble TREM2 protect against Alzheimer's disease?
Brown, G. C., & St George-Hyslop, P. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.834697 · Cited by 39
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
“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 41
“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 42
“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
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
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
Gao, C., Shen, X., Tan, Y., & Chen, S. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02580-1 · Cited by 48
“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 40
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 43
“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 42
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
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 44
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
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 34
“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
“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
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 29
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
“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 32
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- 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 ›
Are you an author, or do you see a problem with this page? Request a review
