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
Items 101–200 of 271
Yang, C., Farias, F. G., Ibáñez, L., Sadler, B. E., Fernández, M. V., Wang, F., Bradley, J. L., Eiffert, B., Bahena, J. A., Budde, J., et al. (2020) · medRxiv · doi:10.1101/2020.06.25.20140277 · Cited by 29
“Although the two genes have been implicated in Alzheimer Disease, Deming et al. (2019) demonstrate for the first time that that MS4A4A interacts with TREM2, and that it is possible to modulate TREM2 levels by targeting MS4A4A levels.”
BackgroundSelf-citationTNFRSF1B Gene Variants and Related Soluble TNFR2 Levels Impact Resilience in Alzheimer’s Disease
Pillai, J. A., Bebek, G., Khrestian, M., Bena, J., Bergmann, C. C., Bush, W. S., Leverenz, J. B., & Bekris, L. M. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.638922 · Cited by 29
Whole exome sequencing analyses identified novel genes for Alzheimer's disease and related dementia
Zhang, Y.-R., Wu, B., Chen, S., Yang, L., Deng, Y., Guo, Y. X., Wu, X., Liu, W., Kang, J., Feng, J., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14181 · Cited by 29
Roles of TREM2 in Alzheimer’s disease
Qi, X., Zhu, K., Ke, W., Wang, J., Mao, S., & Chen, G. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00515-3 · Cited by 38
“The rs1582763 variant correlates with elevated CSF sTREM2 levels and reduced AD risk, whereas the rs6591561 variant is associated with decreased CSF sTREM2 levels and increased AD risk [224, 226].”
New Classification of Macrophages in Plaques: a Revolution
Deng, H., Sun, Y., Zeng, W., Li, H., Guo, M., Yang, L., Lu, B., Yu, B., Fan, G., Gao, Q., et al. (2020) · Current Atherosclerosis Reports · doi:10.1007/s11883-020-00850-y · Cited by 30
Zhuang, X., Jie, L., Song, Y., Ban, R., Zhao, X., Xia, Z., Wang, Z., & Zhang, G. (2024) · NeuroMolecular Medicine · doi:10.1007/s12017-024-08815-z · Cited by 33
“While the exact role of TREM2 in AD is still being clarified, genetic studies suggest that its soluble form may be particularly important (Deming et al., 2019).”
Wang, Q., Schindler, S. E., Chen, G., McKay, N. S., McCullough, A. A., Flores, S. E., Liu, J., Sun, Z., Wang, S., Wang, W., et al. (2024) · Neurology · doi:10.1212/wnl.0000000000208013 · Cited by 27
Self-citationPhospholipase Cγ2 regulates endocannabinoid and eicosanoid networks in innate immune cells
Jing, H., Reed, A., Ulanovskaya, O. A., Grigoleit, J.-S., Herbst, D. M., Henry, C. L., Li, H., Barbas, S., Germain, J., Masuda, K., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2112971118 · Cited by 24
“Additionally, the Ms4a transmembrane family genes, such as Ms4a4a and Ms4a4b, genetic variants of which have been linked to AD risk (50, 51) and have been shown to modulate soluble TREM2 in cerebrospinal fluid (52), were also substantially increased in Plcg2 microglia (Fig.”
BackgroundChanges in the brain transcriptome after DNA Aβ42 trimer immunization in a 3xTg-AD mouse model
Lambracht‐Washington, D., Fu, M., Hynan, L. S., & Rosenberg, R. N. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105221 · Cited by 27
“spanning 4-domains subfamily A (MS4A) protein as an AD risk gene show association with CSF soluble TREM2 concentrations suggestive of modulation of sTREM2 by MS4A (Deming et al., 2019).”
Sheng, X., Yao, Y., Huang, R., Xu, Y., Zhu, Y., Chen, L., Zhang, L., Wang, W., Zhuo, R., Can, D., et al. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02340-7 · Cited by 27
“Higher CSF sTREM2 levels are associated with slower subsequent cognitive and clinical decline in symptomatic AD patients [11, 12].”
BackgroundFernández Zapata, C., Giacomello, G., Spruth, E. J., Middeldorp, J., Gallaccio, G., Dehlinger, A., Dames, C., Leman, J. K. H., van Dijk, R. E., Meisel, A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34719-2 · Cited by 27
Immune dysfunction in Alzheimer disease
Butovsky, O., Rosenzweig, N., Kleemann, K. L., Jorfi, M., Kuchroo, V. K., Tanzi, R. E., & Weiner, H. L. (2025) · Nature reviews. Neuroscience · doi:10.1038/s41583-025-00997-0 · Cited by 41
Li, F., Eteleeb, A. M., Buchser, W., Sohn, C., Wang, G., Xiong, C., Payne, P., McDade, E., Karch, C. M. M., Harari, O., et al. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.935279 · Cited by 27
Self-citationSun, Y., Zhu, J., Yang, Y., Zhang, Z., Zhong, H., Zeng, G., Zhou, D., Nowakowski, R. S., Long, J., Wu, C., et al. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02695-w · Cited by 25
Exploring the Disease-Associated Microglia State in Amyotrophic Lateral Sclerosis
Jauregui, C., Blanco‐Luquin, I., Macías, M., Roldán, M., Caballero, C., Pagola, I., Mendióroz, M., & Jericó, I. (2023) · Biomedicines · doi:10.3390/biomedicines11112994 · Cited by 27
“Genome-wide association studies discovered, in addition to TREM2 , the overexpressed genes in the DAM state selected for this study, TYROBP [39], APOE [40–43], CD33 [44–47] and MS4A [23,45], as AD-associated microglial risk genes [48], but there is less evidence for its involvement in ALS [17,49].”
BackgroundSex Differences in Apolipoprotein E and Alzheimer Disease Pathology Across Ancestries
Xu, X., Kwon, J., Yan, R., Apio, C., Song, S. C., Heo, G., Yang, Q., Timsina, J., Liu, M., Budde, J., et al. (2025) · JAMA Network Open · doi:10.1001/jamanetworkopen.2025.0562 · Cited by 30
Self-citationRe-Exploring the Inflammation-Related Core Genes and Modules in Cerebral Ischemia
Lv, W., Jiang, J., Xu, Y., Chen, Z., Wang, Z., Xing, A., Zheng, X., Qu, T., & Wan, Q. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03275-1 · Cited by 25
You, S., Brase, L., Filipello, F., Iyer, A. K., Del‐Aguila, J. L., He, J., Albanus, R. D., Budde, J., Norton, J. B., Gentsch, J., et al. (2023) · medRxiv · doi:10.1101/2023.02.06.23285545 · Cited by 26
Self-citationWang, R., Zhan, Y., Zhu, W., Yang, Q., & Pei, J. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1407980 · Cited by 25
“The TREM2 H157Y variant (Schlepckow et al., 2017; Qiao et al., 2023), oligomeric A β and the membrane-spanning 4-domain subfamily A (MS4A) gene (Deming et al., 2019) can all increase TREM2 shedding.”
BackgroundInfluentialLin, C., Kong, Y., Chen, Q., Zeng, J., Pan, X., & Miao, J. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1420731 · Cited by 24
Ali, M., Sung, Y. J., Wang, F., Fernández, M. V., Morris, J. C., Fagan, A. M., Blennow, K., Zetterberg, H., Heslegrave, A., Johansson, P., et al. (2022) · PLoS ONE · doi:10.1371/journal.pone.0267298 · Cited by 23
“Interestingly, recent studies [29, 34, 51, 52] have shown that higher sTREM2 levels are associated with lower AD risk and slower progression.”
BackgroundMethodSelf-citationApplying causal discovery to single-cell analyses using CausalCell
Wen, Y., Huang, J., Zhang, H., Guo, S., Elyahu, Y., Monsonego, A., Ding, Y., & Zhu, H. (2023) · eLife · doi:10.7554/elife.81464 · Cited by 24
Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred
Cochran, J. N., Acosta‐Uribe, J., Esposito, B. T., Madrigal, L., Aguillón, D., Giraldo, M. M., Taylor, J. W., Bradley, J., Fulton‐Howard, B., Andrews, S. J., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.13021 · Cited by 21
Self-citationZhao, Y., Guo, Q., Tian, J., Liu, W., & Wang, X. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102596 · Cited by 23
Genetic architecture of plasma Alzheimer disease biomarkers
Bradley, J., Gorijala, P., Schindler, S. E., Sung, Y. J., Ances, B., the Alzheimer’s Disease Neuroimaging Initiative, T. H. C. P., Ertekin-Taner, N., Younkin, S., Golde, T., Price, N., et al. (2023) · Human Molecular Genetics · doi:10.1093/hmg/ddad087 · Cited by 20
Self-citationIdentification of key pathways and core genes involved in atherosclerotic plaque progression
Yang, R., Yao, L., Du, C., & Wu, Y. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-193 · Cited by 21
“Mattiola et al. reported that MS4A4A was induced during the differentiation of monocytes into macrophages (46), while genome-wide association studies have correlated MS4A4A with Alzheimer’s disease and cutaneous systemic sclerosis (47,48).”
Houle, S., & Kokiko‐Cochran, O. N. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.788055 · Cited by 22
“Previous research found that a different SNP, rs1582763, on MS4A4A altered soluble TREM2 (sTREM2) levels in the CSF and GWAS associated this variant with decreased risk for AD (Deming et al., 2019).”
BackgroundQuiroga, I. Y., Cruikshank, A. E., Reed, K. S. M., Bond, M. L., Evangelista, B., Tseng, J., Ragusa, J. V., Meeker, R. B., Won, H., Cohen, S., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02459-1 · Cited by 20
“[47, 48], and ITGAX which has been shown to be upregulated in aged microglia [49, 50].”
BackgroundPhillips, B., Western, D., Wang, L., Timsina, J., Sun, Y.-C., Gorijala, P., Yang, C., Do, A. N., Nykänen, N.-P., Álvarez, I., et al. (2023) · npj Parkinson s Disease · doi:10.1038/s41531-023-00555-4 · Cited by 21
“We identi fi ed a highly signi fi cant trans-pQTL for TREM2 in the MS4A4A region that resolved the MS4A4A loci for AD risk 4 .”
Self-citationD’Oliveira Albanus, R., Finan, G. M., Brase, L., Sweeney, N., Kim, T. Y., Chen, S., Ryoo, Y., Park, J., Guo, Q., Iyer, A. K., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adx0027 · Cited by 19
Self-citationda Rocha, J. F., Lance, M. L., Luo, R., Schlachter, P., Moreira, L., Iqbal, M. A., Kuhn, P., Gardner, R. S., Valaris, S., Islam, M. R., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-01971-w · Cited by 22
Self-citationNordengen, K., Kirsebom, B., Richter, G., Pålhaugen, L., Gísladóttir, B., Siafarikas, N., Nakling, A. E., Rongve, A., Bråthen, G., Grøntvedt, G. R., et al. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02973-w · Cited by 21
Self-citationPark, D. J., Choi, W., Sayeed, S., Dorschner, R. A., Rainaldi, J., Ho, K., Kezios, J., Nolan, J. P., Mali, P., Costantini, T. W., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.02.019 · Cited by 21
Familial and syndromic forms of arachnoid cyst implicate genetic factors in disease pathogenesis
Qureshi, H. M., Mekbib, K. Y., Allington, G., Elsamadicy, A. A., Duy, P. Q., Kundishora, A. J., Jin, S. C., & Kahle, K. T. (2022) · Cerebral Cortex · doi:10.1093/cercor/bhac257 · Cited by 18
Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways
Ibanez, K. R., McFarland, K. N., Phillips, J., Allen, M., Lessard, C. B., Zobel, L., De La Cruz, E. G., Shah, S., Vo, Q., Wang, X., et al. (2022) · Alzheimer's Research & Therapy · doi:10.1186/s13195-022-01044-1 · Cited by 18
Liu, W., Zhang, Y.-R., Ge, Y., Wang, H.-F., Cheng, W., & Yu, J. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03648-6 · Cited by 18
“Moreover, we also found that macrophages in AD occipitotemporal cortex expressed high levels of MS4A - family genes, the essential gene cluster of AD risk [61], and were associated with increasing phagocytosis and immune signaling pathway.”
Targeting Progranulin as an Immuno-Neurology Therapeutic Approach
Boylan, M. A., Pincetic, A., Romano, G. J., Tatton, N. A., Kenkare-Mitra, S., & Rosenthal, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242115946 · Cited by 19
Advances in Genetic and Molecular Understanding of Alzheimer’s Disease
Ibáñez, L., Cruchaga, C., & Fernández, M. V. (2021) · Genes · doi:10.3390/genes12081247 · Cited by 20
Self-citationSánchez‐Ruiz de Gordoa, J., Erro, M. E., Vicuña‐Urriza, J., Zelaya, M. V., Tellechea, P., Acha, B., Zueco, S., Urdánoz‐Casado, A., Roldán, M., Blanco‐Luquin, I., et al. (2020) · Movement Disorders · doi:10.1002/mds.27992 · Cited by 18
“This is consistent with previous studies performed on AD human samples.(14) All of this evidence would suggest that alterations in specific molecular pathways underlying innate immune response may be shared by several brain regions and neurodegenerative conditions.”
BackgroundResultRosner, D., Sun, J., Cacace, R., Yee, A., Wagh, C., Rychkova, A., Dunlap, M., Gulbranson, D. R., Ibrahim, A., Wang, X., et al. (2025) · Neuron · doi:10.1016/j.neuron.2025.11.022 · Cited by 20
Self-citationLi, T., Initiative, A. D. N., Lyu, D., & Liu, F. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220598 · Cited by 17
Role of triggering receptor expressed on myeloid cells 2 (TREM2) in neurodegenerative dementias
Shafi, S., Singh, A., Ibrahim, A. M., Alhajri, N., Izneid, T. A., & Pottoo, F. H. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15215 · Cited by 15
Exosomes in Age-Related Cognitive Decline: Mechanistic Insights and Improving Outcomes
Duggan, M. R., Lu, A., Foster, T. C., Wimmer, M. E., & Parikh, V. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.834775 · Cited by 15
Missing lnc(RNAs) in Alzheimer’s Disease?
Policarpo, R., & d’Ydewalle, C. V. O. (2021) · Genes · doi:10.3390/genes13010039 · Cited by 14
Role of TREM2 in the Development of Neurodegenerative Diseases After Traumatic Brain Injury
Zhang, C., & Chen, S. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03094-w · Cited by 14
Alzheimer’s disease and immunotherapy
Qin, W., Pang, Y., Nie, S., Quan, M., & Jia, J. (2024) · Current Medicine · doi:10.1007/s44194-024-00035-8 · Cited by 15
“Some MSA4 family members could regulate TREM2 receptor activity, suggesting a role for these proteins in the microglia response to AD pathology (Deming et al. 2019).”
Lopes, K. P., Snijders, G. J. L., Humphrey, J., de Witte, L. D., & Raj, T. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.050942 · Cited by 18
Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome
Gorijala, P., Aslam, M. M., Dang, L. T., Xicota, L., Fernandez, M. V., Sung, Y. J., Fan, K., Feingold, E., Surace, E. I., Chhatwal, J. P., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13506 · Cited by 13
Self-citationTowards a Unitary Hypothesis of Alzheimer’s Disease Pathogenesis
Área-Gómez, E., & Schon, E. A. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231318 · Cited by 18
MS4A superfamily molecules in tumors, Alzheimer’s and autoimmune diseases
Luo, X., Luo, B., Fei, L., Zhang, Q., Liang, X., Chen, Y., & Zhou, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1481494 · Cited by 13
Huang, X., Maguire, O. A. B., Walker, J. M., Jiang, C. S., Carroll, T. S., Luo, J., Tonorezos, E. S., Friedman, D. N., & Cohen, P. (2021) · JCI Insight · doi:10.1172/jci.insight.153586 · Cited by 12
“Clusters M-D and M-G express SEPP1 and MS4A6A (Supplemental Figure 5E), macrophage markers that have been studied in a variety of contexts including atherosclerotic plaque formation (33), tumor infiltration (34, 35), and Alzheimer’s disease (36).”
Variants in the MS4A cluster interact with soluble TREM2 expression on biomarkers of neuropathology
Winfree, R. L., Nolan, E., Dumitrescu, L. C., Blennow, K., Zetterberg, H., Gifford, K. A., Pechman, K. R., Seto, M., Petyuk, V., Wang, Y., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00727-7 · Cited by 12
“Interestingly, emerging genomic and functional evidence has suggested that these two genomic regions may interact or converge on a common disease pathway with myeloid lineage cells [10].”
BackgroundResultInfluentialSelf-citationParrish, R. L., Buchman, A. S., Tasaki, S., Wang, Y., Avey, D. R., Xu, J., Jager, P. L. D., Bennett, D. A. A., Epstein, M. P., & Yang, J. (2024) · Nature Communications · doi:10.1038/s41467-024-50983-w · Cited by 14
“SRD5A3P is located in theAD-associated MS4A gene cluster 27 , which containsmultiple known GWAS risk genes 19,21 – 23 as well as TWAS risk gene MS4A2 20 of AD.”
BackgroundCómitre-Mariano, B., Vellila-Alonso, G., Segura‐Collar, B., Mondéjar-Ruescas, L., Sepúlveda-Sánchez, J. M., & Gargini, R. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03298-y · Cited by 16
İş, Ö., Min, Y., Wang, X., Oatman, S. R., Daniel, A. A., & Ertekin‐Taner, N. (2024) · Glia · doi:10.1002/glia.24652 · Cited by 13
Functional insight into LOAD-associated microglial response genes
Jonas, L. A., Jain, T., & Li, Y. (2022) · Open Biology · doi:10.1098/rsob.210280 · Cited by 13
Zhou, W., Zhou, Y., & Li, J. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12103589 · Cited by 12
Identification of common core ion channel genes in epilepsy and Alzheimer’s disease
Tang, T. S., Li, X., Yu, E., Li, M., & Pan, X. (2023) · Irish Journal of Medical Science (1971 -) · doi:10.1007/s11845-023-03447-x · Cited by 12
Jiao, H., Ge, Y., Huang, L.-Y., Liu, Y., Wu, B., Lian, P., Hao, Y., Han, S., Li, Y., Wu, K., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00887-0 · Cited by 11
“This is consistent with prior reports of coordinated MS4A-TREM2 upregulation in protective microglial states [12], supporting the potential protective effect of MS4A6A upregulation.”
InfluentialHuang, Z. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221042 · Cited by 12
From odor to oncology: non-canonical odorant receptors in cancer
Park, S. J., Greer, P. L., & Lee, N. (2023) · Oncogene · doi:10.1038/s41388-023-02908-y · Cited by 12
“MS4A4A and MS4A6A are present in microglia within the brain, whereas MS4A7 is considered an ontogeny marker due to its high expression in microglia-like macrophages resembling microglia in disease states, such as neurodegenerative diseases, in the brain [72 – 74].”
Park, Y., He, L., Dávila-Velderrain, J., Hou, L., Mohammadi, S., Mathys, H., Peng, Z., Bennett, D. A., Tsai, L., & Kellis, M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.01.21.426000 · Cited by 11
Basic Microglial Functions and How They Go Awry in Neurodegenerative Disease
McKinney, J. E., Bennett, M. L., & Bennett, F. C. (2026) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-042624-114332 · Cited by 13
Wickstead, E. S., Irving, M. A., Getting, S. J., & McArthur, S. (2021) · FEBS Journal · doi:10.1111/febs.15861 · Cited by 10
RNASE6 is a novel modifier of APOE-ε4 effects on cognition
Seto, M., Weiner, R. L., Dumitrescu, L. C., Mahoney, E. R., Hansen, S., Janve, V. A., Khan, O. A., Liu, D., Wang, Y., Menon, V., et al. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.06.011 · Cited by 11
Liver-Specific Polygenic Risk Score Is Associated with Alzheimer’s Disease Diagnosis
Panyard, D. J., Deming, Y. K., Darst, B. F., Hulle, C. A. V., Zetterberg, H., Blennow, K., Kollmorgen, G., Suridjan, I., Carlsson, C. M., Johnson, S. C., et al. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-220599 · Cited by 10
Self-citationA landscape of the genetic and cellular heterogeneity in Alzheimer diseasePreprint
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. (2021) · medRxiv · doi:10.1101/2021.11.30.21267072 · Cited by 11
Self-citationAvalos, B., Kulbe, J. R., Ford, M. K., Laird, A. E., Walter, K., Mante, M., Florio, J. B., Boustani, A., Chaillon, A., Schlachetzki, J. C. M., et al. (2024) · Viruses · doi:10.3390/v16101509 · Cited by 11
“It is plausible that genetic mutations and exposure to viral infection may initiate inflammatory cascades upstream of AD pathogenesis, much like the potential mechanisms controlling TREM2 dysfunction [82,83].”
Background15 years of longitudinal genetic, clinical, cognitive, imaging, and biochemical measures in DIAN
Daniels, A. J., McDade, E., Llibre‐Guerra, J. J., Xiong, C., Perrin, R. J., Ibáñez, L., Supnet‐Bell, C., Cruchaga, C., Goate, A., Renton, A. E., et al. (2026) · npj Dementia · doi:10.1038/s44400-025-00047-7 · Cited by 11
Self-citationTREM2splicing emerges as crucial aspect to understand TREM2 biology
Moutinho, M., & Landreth, G. E. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.2ce0521-264r · Cited by 10
Cardona, C. L., Wei, L., Kim, J., Angeles, E., Singh, G., Chen, S., Patel, R., Ifediora, N., Canoll, P., Teich, A. F., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03562-9 · Cited by 8
Yuan, Y., Hu, R., Chen, S., Zhang, X. H., Liu, Z., & Zhou, G. (2024) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2024.108612 · Cited by 8
Genome-Wide Landscape of North-Eastern European Populations: A View from Lithuania
Urnikytė, A., Molytė, A., & Kučinskas, V. (2021) · Genes · doi:10.3390/genes12111730 · Cited by 8
“Such signals point to the MS4A4A gene and non-synonymous variant rs659156, which are associated with reduced CSF sTREM2 (soluble triggering receptor expressed on myeloid cells 2) [33], increased Alzheimer’s disease (AD) risk [34], and accelerated age-at-onset AD [35].”
BackgroundHu, S., Pan, N., Liu, C., Wang, Y., & Zhang, T. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.775432 · Cited by 8
Hillary, R. F., Gadd, D. A., McCartney, D. L., Shi, L., Campbell, A., Walker, R. M., Ritchie, C. W., Deary, I. J., Evans, K. L., Nevado‐Holgado, A. J., et al. (2022) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12280 · Cited by 10
“In a strategy that used human macrophages as proxies for microglia, this polymorphism was shown to alter MS4A4A expression and subsequently modulate TREM2 concentration (67).”
MethodNetwork Dynamics‐based Subtyping of Alzheimer's Disease With Microglial Genetic Risk Factors
Choi, J. H., Lee, J., Kang, U., Chang, H., & Cho, K.-H. (2024) · Alzheimer's Research & Therapy · doi:10.1186/s13195-024-01583-9 · Cited by 7
Glial Cells in Alzheimer’s Disease: Pathogenic Mechanisms and Therapeutic Frontiers
Sil, M., Mukherjee, N., Chatterjee, I., Ghosh, A., & Goswami, A. (2025) · Journal of Molecular Neuroscience · doi:10.1007/s12031-025-02379-8 · Cited by 9
Bradley, J. L., Pottier, C. P., da Fonseca, E. L., Kurup, J. T., Western, D., Wang, C., Neupane, A., Ray, N. R., Jean‐Francois, M. N., Ali, M., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70377 · Cited by 9
Self-citationCoupling of Alzheimer’s Disease Genetic Risk Factors with Viral Susceptibility and Inflammation
Cao, C., Fu, G., Xu, R., & Li, N. (2023) · Aging and Disease · doi:10.14336/ad.2023.1017 · Cited by 8
Research momentum brings hope for dementia in 2019
Schneider, J. A. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(19)30453-3 · Cited by 7
Li, F., Eteleeb, A. M., Buchser, W., Wang, G., Xiong, C., Payne, P., McDade, E., Karch, C. M. M., Harari, O., & Cruchaga, C. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.30.458295 · Cited by 7
Self-citationTesi, N., van der Lee, S. J., Hulsman, M., van Schoor, N. M., Huisman, M. A., Pijnenburg, Y. A. L., van der Flier, W. M., Reinders, M. J. T., & Holstege, H. H. (2023) · medRxiv · doi:10.1101/2023.05.16.23290049 · Cited by 8
“[42] Specifically, ABCA7 gene is involved in beta-amyloid processing and clearance, while SORL1 gene”
BackgroundMs4a4a deficiency ameliorates plaque pathology in a mouse model of amyloid accumulation
Danhash, E., Verbeck, A. C., Western, D., Díaz‐Pacheco, A. S., Galasso, G., You, S., Huang, G., Starr, E., Miller, N., Nadarajah, C. J., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70580 · Cited by 6
Self-citationBoutet, M., Mattiola, I., Silva-Gomes, R., Nerviani, A., Sironi, M., Ghirardi, G. M., Troilo, A., Gianoli, S., Rivellese, F., Çubuk, C., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2504529122 · Cited by 7
“In particular, we previously demonstrated that MS4A4A associates with Dectin - 1 (24), and others have reported its association with TREM - 2 (25).”
Acquired immunity and Alzheimer's disease
Feng, W., Zhang, Y., Sun, P. G., & Xiao, M. (2022) · Journal of Biomedical Research · doi:10.7555/jbr.36.20220083 · Cited by 9
Clarkson, T. C., Iguchi, N., Xie, A. X., & Malykhina, A. P. (2022) · PLoS ONE · doi:10.1371/journal.pone.0278918 · Cited by 6
Su, C., Zhang, J., & Zhao, H. (2023) · Journal of the American Statistical Association · doi:10.1080/01621459.2023.2297467 · Cited by 6
“, 2013); MS4A gene cluster is a key modulator of TREM2 in microglia (Deming et al., 2019) and SPI1 is a central regulator of microglia expression and Alzheimer’s disease risk (Kosoy et al.”
BackgroundJi, Y., McLean, J. L., & Xu, R. (2024) · Neuroscience Bulletin · doi:10.1007/s12264-024-01189-z · Cited by 8
“These analyses have also identified several microglia-specific genes, including Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and Membrane-spanning 4-domains subfamily A (MS4A), whose expression is regulated during disease progression [78, 79].”
Screening for Core Genes Related to Pathogenesis of Alzheimer’s Disease
Yang, L.-X., Qin, Y. H., & Jian, C. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.668738 · Cited by 7
“For instance, MS4A and somatic APP are involved in the above pathways to influence AD pathogenesis (Lee et al., 2018; Deming et al., 2019).”
BackgroundFongang, B., Sargurupremraj, M., Jian, X., Mishra, A., Damotte, V., Bis, J. C., Kang-Hsien, F., Li, G., Yang, J., Hilal, S., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.11.509802 · Cited by 6
Warwick, A., Hingorani, A. D., Khawaja, A. P., Gordillo‐Marañón, M., Olvera‐Barrios, A., Stuart, K. V., Egan, C. A., Tufail, A., Sofat, R., Kuan, V., et al. (2024) · medRxiv · doi:10.1101/2024.07.11.24310200 · Cited by 4
Microglial MS4A4A Protects against Epileptic Seizures in Alzheimer's Disease
Jiang, M., Li, Q., Chen, J., Li, R., Yao, J., Hu, Y., Zhang, H., Cai, L., Luo, M., Sun, Y., et al. (2025) · Advanced Science · doi:10.1002/advs.202417733 · Cited by 6
Parithathvi, A., Harshitha, P., Mumbrekar, K. D., & Dsouza, H. S. (2025) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-025-01613-6 · Cited by 6
The late-onset Alzheimer’s disease risk factor RHBDF2 is a modifier of microglial TREM2 proteolysis
Jocher, G., Müller, S. A., Hsia, H., Osua, M. L., Özcelik, G., Hofmann, L. I., Aßfalg, M., Dinkel, L., Feng, X. M., Schlepckow, K., et al. (2025) · Life Science Alliance · doi:10.26508/lsa.202403080 · Cited by 6
Self-citationSek, A. C., Percopo, C. M., Boddapati, A. K., Ma, M., Geslewitz, W. E., Krumholz, J. O., Lack, J., & Rosenberg, H. F. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.3a0920-620r · Cited by 5
Mulvey, B., Lagunas, T., & Dougherty, J. D. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.02.02.931337 · Cited by 4
Connecting dementia risk loci to the CSF proteome identifies pathophysiological leads for dementia
Reus, L. M., Jansen, I. E., Tijms, B. M., Visser, P. J., Tesi, N., van der Lee, S. J., Vermunt, L., Peeters, C. F. W., Groot, L. A. D., Hok‐A‐Hin, Y. S., et al. (2024) · Brain · doi:10.1093/brain/awae090 · Cited by 6
“26 The integration of genetic data with the CSF proteome has improved our understanding of the gene regulatory landscape underlying dementia, 27-29 as illustrated by the cis and trans effects of AD risk factors APOE - ɛ 4 29 and MS4A 30 and trans effects of FTD risk factor TMEM106B on neurofilament light.”
BackgroundHan, S., Cho, S.-A., Choi, W., Eilbeck, K. L., Coon, H. H., Nho, K. T., & Lee, Y. (2025) · BMC Genomics · doi:10.1186/s12864-025-11362-x · Cited by 6
“Other studies have highlighted SNP-regu-lated expressions in AD-risk genes including PLIN2 [24], MS4A [30], MAPT [31], and CR1 [32].”
Baumgartner, A. M., Robinson, M., Ertekin‐Taner, N., Golde, T. E., Jayadev, S., Huang, S., Hadlock, J., & Funk, C. C. (2025) · Communications Biology · doi:10.1038/s42003-025-07594-y · Cited by 4
Identification of potential key genes and immune infiltration in Multiple sclerosis
Liu, Y., Zhou, Y., Yue, H., Dou, H., Rang, X., Wang, X., Xu, C., & Fu, J. (2022) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2022.103748 · Cited by 4
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
