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Cited by 2Alzheimer's disease research and treatmentsSystemic Lupus Erythematosus ResearchMonoclonal and Polyclonal Antibodies Research

Large-scale seroepidemiology uncovers nephro-urological pathologies in people with tau autoimmunity

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Magalhães, Andreia D., Emmenegger, Marc, De Cecco, Elena, Carta, Manfredi, Frontzek, Karl, Chincisan, Andra, Guo, Jingjing, Hornemann, Simone +1 more·2025·PLOS Biology
DOI 10.1371/journal.pbio.3003488PMC PMC12685212
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Abstract

Intraneuronal aggregates of the microtubule-associated protein tau play a pivotal role in Alzheimer’s disease and several other neurodegenerative syndromes. Anti-tau antibodies can reduce pathology in mouse models of neurodegeneration and are currently being tested in humans. Here, we performed a large-scale seroepidemiological search for anti-tau IgG autoantibodies (ατ) on 40,497 human plasma samples. High-titer ατ + individuals were surprisingly prevalent, with hospital patients being three times more likely to be ατ + (EC 50 ≥ 2 6 ; a nominal dilution of >1/64) than healthy blood donors (4.8% versus 1.6%). The prevalence increased with age over 70 years-old (RR 1.26, 95% CI 1.11–1.43, P < 0.001) and was higher for women (RR 1.20, 95% CI 1.07–1.39, P = 0.002). The autoantibodies bound selectively to tau, inhibited tau aggregation in vitro, and interfered with tau detection in plasma samples. No association was found between ατ autoantibodies and neurological disorders. Instead, tau autoreactivity showed a significant association with kidney and urinary disorders (adjusted RR 1.27, 95% CI 1.10–1.45, P = 0.001 and 1.40, 95% CI 1.20–1.63, P < 0.001, respectively). These results suggest a previously unrecognized association between ατ autoimmunity and extraneural diseases.

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  • Naturally occurring anti-tau antibodies are detected in both AD patients and healthy controls without significant inter-group differences in their levels or correlation with cognitive decline.

    “naturally occurring anti-tau antibodies are detected in both AD patients and healthy controls without significant inter-group differences in their levels or correlation with cognitive decline”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [101]

    The Introduction reports anti-tau antibodies in people with AD and in non-neurodegeneration controls. The Results section ‘Neurological disorders and anti-tau autoimmunity’ reports no significant difference in antibody reactivity between 47 AD patients and 68 similarly aged non-AD patients, but does not establish that those comparators were healthy or test a correlation between antibody levels and cognitive decline. (LLM, conf=0.88)

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Research works printed but not linked: 54

  1. [1]Gu Y, Oyama F, Ihara Y. Tau is widely expressed in rat tissues. J Neurochem. 1996; 67(3): 1235– 44. doi: 10.1046/j.1471-4159.1996.67031235.x 8752131 · DOI
  2. [2]Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220): 1260419. doi: 10.1126/science.1260419 25613900 · DOI · Paper page
  3. [3]Sotiropoulos I, Galas M-C, Silva JM, Skoulakis E, Wegmann S, Maina MB, et al. Atypical, non-standard functions of the microtubule associated Tau protein. Acta Neuropathol Commun. 2017; 5(1): 91. doi: 10.1186/s40478-017-0489-6 29187252 PMC5707803 · DOI
  4. [5]Ho K-H, Yang X, Osipovich AB, Cabrera O, Hayashi ML, Magnuson MA, et al. Glucose regulates microtubule disassembly and the dose of insulin secretion via tau phosphorylation. Diabetes. 2020; 69(9): 1936– 47. doi: 10.2337/db19-1186 32540877 PMC7458041 · DOI
  5. [6]Kosik KS, Joachim CL, Selkoe DJ. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A. 1986; 83(11): 4044– 8. 2424016 PMC323662
  6. [7]Joachim CL, Morris JH, Kosik KS, Selkoe DJ. Tau antisera recognize neurofibrillary tangles in a range of neurodegenerative disorders. Ann Neurol. 1987; 22(4): 514– 20. doi: 10.1002/ana.410220411 2963585 · DOI
  7. [8]Hanseeuw BJ, Betensky RA, Jacobs HIL, Schultz AP, Sepulcre J, Becker JA, et al. Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol. 2019; 76(8): 915– 24. doi: 10.1001/jamaneurol.2019.1424 31157827 PMC6547132 · DOI · Paper page
  8. [9]Mattsson N, Zetterberg H, Janelidze S, Insel PS, Andreasson U, Stomrud E, et al. Plasma tau in Alzheimer disease. Neurology. 2016; 87(17): 1827– 35. doi: 10.1212/WNL.0000000000003246 27694257 PMC5089525 · DOI · Paper page
  9. [10]Janelidze S, Mattsson N, Palmqvist S, Smith R, Beach TG, Serrano GE, et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med. 2020; 26(3): 379– 86. doi: 10.1038/s41591-020-0755-1 32123385 · DOI · Paper page
  10. [11]Mielke MM, Hagen CE, Wennberg AMV, Airey DC, Savica R, Knopman DS, et al. Association of plasma total tau level with cognitive decline and risk of mild cognitive impairment or dementia in the mayo clinic study on aging. JAMA Neurol. 2017; 74(9): 1073– 80. doi: 10.1001/jamaneurol.2017.1359 28692710 PMC5710182 · DOI
  11. [12]Palmqvist S, Tideman P, Mattsson-Carlgren N, Schindler SE, Smith R, Ossenkoppele R, et al. Blood biomarkers to detect Alzheimer disease in primary care and secondary care. JAMA. 2024; 332(15): 1245– 57. doi: 10.1001/jama.2024.13855 39068545 PMC11284636 · DOI · Paper page
  12. [13]Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci. 2007; 27(34): 9115– 29. doi: 10.1523/JNEUROSCI.2361-07.2007 17715348 PMC6672191 · DOI · Paper page
  13. [16]Rothstein TL. Natural antibodies as rheostats for susceptibility to chronic diseases in the aged. Front Immunol. 2016; 7: 127. doi: 10.3389/fimmu.2016.00127 27092140 PMC4823301 · DOI
  14. [17]Lutz HU, Binder CJ, Kaveri S. Naturally occurring auto-antibodies in homeostasis and disease. Trends Immunol. 2009; 30(1): 43– 51. doi: 10.1016/j.it.2008.10.002 19058756 · DOI
  15. [18]Bastard P, Gervais A, Le Voyer T, Rosain J, Philippot Q, Manry J, et al. Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths. Sci Immunol. 2021; 6(62):eabl4340. doi: 10.1126/sciimmunol.abl4340 34413139 PMC8521484 · DOI
  16. [19]Jaycox JR, Dai Y, Ring AM. Decoding the autoantibody reactome. Science. 2024; 383(6684): 705– 7. doi: 10.1126/science.abn1034 38359108 · DOI
  17. [20]Florance NR, Davis RL, Lam C, Szperka C, Zhou L, Ahmad S, et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol. 2009; 66(1): 11– 8. doi: 10.1002/ana.21756 19670433 PMC2826225 · DOI · Paper page
  18. [21]Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004; 364(9451): 2106– 12. doi: 10.1016/S0140-6736(04)17551-X 15589308 · DOI · Paper page
  19. [24]Kronimus Y, Albus A, Balzer-Geldsetzer M, Straub S, Semler E, Otto M, et al. Naturally occurring autoantibodies against tau protein are reduced in Parkinson’s disease dementia. PLoS One. 2016; 11(11):e0164953. doi: 10.1371/journal.pone.0164953 27802290 PMC5089716 · DOI
  20. [25]Emmenegger M, De Cecco E, Lamparter D, Jacquat RPB, Riou J, Menges D, et al. Continuous population-level monitoring of SARS-CoV-2 seroprevalence in a large European metropolitan region. iScience. 2023; 26(2): 105928. doi: 10.1016/j.isci.2023.105928 36619367 PMC9811913 · DOI
  21. [26]Emmenegger M, Zografou C, Yile D, Hoyt LR, Gudneppanavar R, Chincisan A, et al. The cystic fibrosis transmembrane regulator controls tolerogenic responses to food allergens in mice and humans. medRxiv. 2024. doi: 10.1101/2024.06.17.24309019 · DOI
  22. [27]Senatore A, Frontzek K, Emmenegger M, Chincisan A, Losa M, Reimann R, et al. Protective anti-prion antibodies in human immunoglobulin repertoires. EMBO Mol Med. 2020; 12(9):e12739. doi: 10.15252/emmm.202012739 32776637 PMC7506995 · DOI
  23. [28]Diaz-Quijano FA. A simple method for estimating relative risk using logistic regression. BMC Med Res Methodol. 2012; 12: 14. doi: 10.1186/1471-2288-12-14 22335836 PMC3305608 · DOI
  24. [29]Donoghoe MW, Marschner IC. logbin: an R package for relative risk regression using the log-binomial model. J Stat Soft. 2018; 86(9). doi: 10.18637/jss.v086.i09 · DOI
  25. [30]de Silva R, Lashley T, Gibb G, Hanger D, Hope A, Reid A, et al. Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies. Neuropathol Appl Neurobiol. 2003; 29(3): 288– 302. doi: 10.1046/j.1365-2990.2003.00463.x 12787326 · DOI
  26. [31]Apetri A, Crespo R, Juraszek J, Pascual G, Janson R, Zhu X, et al. A common antigenic motif recognized by naturally occurring human VH5-51/VL4-1 anti-tau antibodies with distinct functionalities. Acta Neuropathol Commun. 2018; 6(1): 43. doi: 10.1186/s40478-018-0543-z 29855358 PMC5984341 · DOI
  27. [32]Pase MP, Beiser AS, Himali JJ, Satizabal CL, Aparicio HJ, DeCarli C, et al. Assessment of plasma total tau level as a predictive biomarker for dementia and related endophenotypes. JAMA Neurol. 2019; 76(5): 598– 606. doi: 10.1001/jamaneurol.2018.4666 30830207 PMC6515589 · DOI
  28. [33]Barini E, Plotzky G, Mordashova Y, Hoppe J, Rodriguez-Correa E, Julier S, et al. Tau in the brain interstitial fluid is fragmented and seeding-competent. Neurobiol Aging. 2022; 109: 64– 77. doi: 10.1016/j.neurobiolaging.2021.09.013 34655982 · DOI
  29. [34]Dahm L, Ott C, Steiner J, Stepniak B, Teegen B, Saschenbrecker S, et al. Seroprevalence of autoantibodies against brain antigens in health and disease. Ann Neurol. 2014; 76(1): 82– 94. doi: 10.1002/ana.24189 24853231 · DOI
  30. [35]Yu Z-Y, Li W-W, Yang H-M, Mañucat-Tan NB, Wang J, Wang Y-R, et al. Naturally occurring antibodies to tau exists in human blood and are not changed in Alzheimer’s disease. Neurotox Res. 2020; 37(4): 1029– 35. doi: 10.1007/s12640-020-00161-9 32026360 · DOI · Paper page
  31. [36]Tsuboi Y, Uitti RJ, Delisle M-B, Ferreira JJ, Brefel-Courbon C, Rascol O, et al. Clinical features and disease haplotypes of individuals with the N279K tau gene mutation: a comparison of the pallidopontonigral degeneration kindred and a French family. Arch Neurol. 2002; 59(6): 943– 50. doi: 10.1001/archneur.59.6.943 12056930 · DOI
  32. [37]Vallés-Saiz L, Peinado-Cahuchola R, Ávila J, Hernández F. Microtubule-associated protein tau in murine kidney: role in podocyte architecture. Cell Mol Life Sci. 2022; 79(2): 97. doi: 10.1007/s00018-021-04106-z 35084555 PMC8794918 · DOI
  33. [40]Barton ME, Steen BVD, Van Tricht HLG, Byrnes W, Purcell FE, Southcott SA, et al. Update on the TOGETHER study: a patient‐ and investigator‐blind, randomized, placebo‐controlled study evaluating the efficacy, safety and tolerability of bepranemab, UCB0107, in prodromal‐to‐mild Alzheimer’s disease. Alzheimer’s Dementia. 2022; 18(S10). doi: 10.1002/alz.068973 · DOI
  34. [41]Moscoso A, Grothe MJ, Ashton NJ, Karikari TK, Lantero Rodríguez J, Snellman A, et al. Longitudinal associations of blood phosphorylated tau181 and neurofilament light chain with neurodegeneration in Alzheimer disease. JAMA Neurol. 2021; 78(4): 396– 406. doi: 10.1001/jamaneurol.2020.4986 33427873 PMC7802009 · DOI
  35. [42]Barthélemy NR, Li Y, Joseph-Mathurin N, Gordon BA, Hassenstab J, Benzinger TLS, et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat Med. 2020; 26(3): 398– 407. doi: 10.1038/s41591-020-0781-z 32161412 PMC7309367 · DOI · Paper page
  36. [43]Karikari TK, Pascoal TA, Ashton NJ, Janelidze S, Benedet AL, Rodriguez JL, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020; 19(5): 422– 33. doi: 10.1016/S1474-4422(20)30071-5 32333900 · DOI · Paper page
  37. [44]Park J-C, Han S-H, Yi D, Byun MS, Lee JH, Jang S, et al. Plasma tau/amyloid-β1-42 ratio predicts brain tau deposition and neurodegeneration in Alzheimer’s disease. Brain. 2019; 142(3): 771– 86. doi: 10.1093/brain/awy347 30668647 · DOI
  38. [45]Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA. 2020; 324(8): 772– 81. doi: 10.1001/jama.2020.12134 32722745 PMC7388060 · DOI · Paper page
  39. [46]Yanamandra K, Patel TK, Jiang H, Schindler S, Ulrich JD, Boxer AL, et al. Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy. Sci Transl Med. 2017; 9(386):eaal2029. doi: 10.1126/scitranslmed.aal2029 28424326 PMC5727571 · DOI · Paper page
  40. [47]Mielke MM, Dage JL, Frank RD, Algeciras-Schimnich A, Knopman DS, Lowe VJ, et al. Performance of plasma phosphorylated tau 181 and 217 in the community. Nat Med. 2022; 28(7): 1398– 405. doi: 10.1038/s41591-022-01822-2 35618838 PMC9329262 · DOI · Paper page
  41. [48]St Germaine-Smith C, Metcalfe A, Pringsheim T, Roberts JI, Beck CA, Hemmelgarn BR, et al. Recommendations for optimal ICD codes to study neurologic conditions: a systematic review. Neurology. 2012; 79(10): 1049– 55. doi: 10.1212/WNL.0b013e3182684707 22914826 PMC3430709 · DOI
  42. [49]Fischer I. Big tau: what we know, and we need to know. eNeuro. 2023; 10(5). PMC10179842 37164636
  43. [50]Meng J, Lei P. Plasma pTau181 as a biomarker for Alzheimer’s disease. MedComm (2020). 2020; 1(1): 74– 6. doi: 10.1002/mco2.1 34766110 PMC8489665 · DOI
  44. [51]Telser J, Risch L, Saely CH, Grossmann K, Werner P. P-tau217 in Alzheimer’s disease. Clin Chim Acta. 2022; 531: 100– 11. doi: 10.1016/j.cca.2022.03.018 35341762 · DOI
  45. [52]Gonzalez-Ortiz F, Turton M, Kac PR, Smirnov D, Premi E, Ghidoni R, et al. Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration. Brain. 2023; 146(3): 1152– 65. doi: 10.1093/brain/awac407 36572122 PMC9976981 · DOI
  46. [54]Hedgepeth CM, Conrad LJ, Zhang J, Huang HC, Lee VM, Klein PS. Activation of the Wnt signaling pathway: a molecular mechanism for lithium action. Dev Biol. 1997; 185(1): 82– 91. 9169052
  47. [55]Bunker JJ, Erickson SA, Flynn TM, Henry C, Koval JC, Meisel M, et al. Natural polyreactive IgA antibodies coat the intestinal microbiota. Science. 2017; 358(6361):eaan6619. doi: 10.1126/science.aan6619 28971969 PMC5790183 · DOI
  48. [56]Mouquet H, Scheid JF, Zoller MJ, Krogsgaard M, Ott RG, Shukair S, et al. Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation. Nature. 2010; 467(7315): 591– 5. doi: 10.1038/nature09385 20882016 PMC3699875 · DOI
  49. [57]Emmenegger M, De Cecco E, Hruska-Plochan M, Eninger T, Schneider MM, Barth M, et al. LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies. EMBO Mol Med. 2021; 13(9):e14745. doi: 10.15252/emmm.202114745 34309222 PMC8422075 · DOI
  50. [58]Losa M, Emmenegger M, De Rossi P, Schürch PM, Serdiuk T, Pengo N, et al. The ASC inflammasome adapter governs SAA-derived protein aggregation in inflammatory amyloidosis. EMBO Mol Med. 2024; 16(9): 2024– 42. doi: 10.1038/s44321-024-00107-0 39080493 PMC11393341 · DOI
  51. [59]Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010; 68(6): 1067– 81. doi: 10.1016/j.neuron.2010.11.030 21172610 PMC3026458 · DOI · Paper page
  52. [60]Orrú CD, Yuan J, Appleby BS, Li B, Li Y, Winner D, et al. Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease. Sci Transl Med. 2017; 9(417):eaam7785. doi: 10.1126/scitranslmed.aam7785 29167394 PMC5744860 · DOI
  53. [61]McNutt L-A, Wu C, Xue X, Hafner JP. Estimating the relative risk in cohort studies and clinical trials of common outcomes. Am J Epidemiol. 2003; 157(10): 940– 3. doi: 10.1093/aje/kwg074 12746247 · DOI
  54. [62]Emmenegger M, Emmenegger V, Shambat SM, Scheier TC, Gomez-Mejia A, Chang C-C, et al. Antiphospholipid antibodies are enriched post-acute COVID-19 but do not modulate the thrombotic risk. Clin Immunol. 2023; 257: 109845. doi: 10.1016/j.clim.2023.109845 37995947 · DOI

Cited by

Sorted by citations

Authors
Magalhães, A. D., Emmenegger, M., De Cecco, E., Carta, M., Frontzek, K., Chincisan, A., Guo, J., Hornemann, S., & Aguzzi, A.
Affiliations
University of Zurich (CH)
Corresponding author
  • Hornemann, Simone
  • Aguzzi, Adriano
ORCID
Venue
PLOS Biology
Publisher
Public Library of Science (PLoS)
Published
2025-11-26
Volume
23
Issue
11
Pages
e3003488
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.3003488
PMC
PMC12685212
OpenAlex
W4416786583
Cited by
2
References
6
Citations by year
2026: 2
FWCI
1.29
Type
journal article
Language
en
Update notices
new_version (2025-12-08)
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • UZH Foundation (FK-10-025)
  • Swiss Personalized Health Network (2017DRI17)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (179040, 207872, 183563)
  • European Research Council (670958ERC)
  • NOMIS Stiftung
  • Universitätsspital Zürich (CH); Innovation Fund (INOV00096)
  • Universitätsspital Zürich (CH); Foundation Grant (USZF27101)
  • HMZ Immunotarget
  • Stiftung Neuropath
  • Fondazione Gelu
  • Michael J. Fox Foundation for Parkinson's Research (MJFF-020710, MJFF-021073)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
Keywords
seroepidemiology, kidney disease, urinary disorders, sex differences, age-related prevalence
MeSH terms
Adult, Aged, Aged, 80 and over, Autoantibodies, Female, Humans, Immunoglobulin G, Kidney Diseases, Male, Middle Aged, Autoimmunity, Seroepidemiologic Studies, tau Proteins

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