CoChat
Sign Up
Cited by 127Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease

Open access
Meisl, Georg, Hidari, Eric, Allinson, Kieren, Rittman, Timothy, DeVos, Sarah L., Sanchez, Justin S., Xu, Catherine K., Duff, Karen E. +5 more·2021·Science Advances
DOI 10.1126/sciadv.abh1448PMC PMC8555892
Open this paper in CoChat — free account

Abstract

Local replication doubles the number of tau aggregate in Alzheimer’s disease only once every 5 years, limiting the overall rate.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1126/sciadv.abh1448

Cites

10 of 10 references verified0 citation errors · 0 not checkable

Statistics

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.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Pathology aggregates exponentially in AD.

    “Inspired by biophysical studies45, which suggest that pathology aggregates exponentially in AD, we constructed a Bayesian model to infer AD pathological burden from the trajectory of each quantifiable neuropathological variable.”

    From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [45]

    The Results section, “Tau seeds in AD have a doubling time of approximately 5 years” (page unavailable), reports an approximately five-year doubling time for tau seeds and aggregates in human AD, consistent with exponential accumulation. But the analysis focuses on tau pathology, particularly later Braak stages; it does not establish exponential accumulation for AD pathology generally or for every neuropathological variable. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 31

  1. [1]F. Chiti, C. M. Dobson, Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 75, 333– 366 (2006). 16756495
  2. [4]R. E. Bennett, S. L. De Vos, S. Dujardin, B. Corjuc, R. Gor, J. Gonzalez, A. D. Roe, M. P. Frosch, R. Pitstick, G. A. Carlson, B. T. Hyman, Enhanced tau aggregation in the presence of amyloid β. Am. J. Pathol. 187, 1601– 1612 (2017). 28500862 PMC5500829
  3. [5]M. Iba, J. L. Guo, J. D. McBride, B. Zhang, J. Q. Trojanowski, V. M.-Y. Lee, Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of alzheimer’s-like tauopathy. J. Neurosci. 33, 1024– 1037 (2013). 23325240 PMC3575082
  4. [7]F. Clavaguera, H. Akatsu, G. Fraser, R. Anthony Crowther, S. Frank, J. Hench, A. Probst, D. T. Winkler, J. Reichwald, M. Staufenbiel, B. Ghetti, M. Goedert, M. Tolnay, Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl. Acad. Sci. U.S.A. 110, 9535– 9540 (2013). 23690619 PMC3677441
  5. [8]L. Liu, V. Drouet, J. W. Wu, M. P. Witter, S. A. Small, C. Clelland, K. Duff, Trans-synaptic spread of tau pathology in vivo. PLOS ONE 7, e31302 (2012). 22312444 PMC3270029
  6. [9]S. Dujardin, C. Commins, A. Lathuiliere, P. Beerepoot, A. R. Fernandes, T. V. Kamath, M. B. De Los Santos, N. Klickstein, D. L. Corjuc, B. T. Corjuc, P. M. Dooley, A. Viode, D. H. Oakley, B. D. Moore, K. Mullin, D. Jean-Gilles, R. Clark, K. Atchison, R. Moore, L. B. Chibnik, R. E. Tanzi, M. P. Frosch, A. Serrano-Pozo, F. Elwood, J. A. Steen, M. E. Kennedy, B. T. Hyman, Tau molecular diversity contributes to clinical heterogeneity in alzheimer’s disease. Nat. Med. 26, 1256– 1263 (2020). 32572268 PMC7603860
  7. [10]H. Fu, S. Abid Hussaini, S. Wegmann, C. Profaci, J. D. Daniels, M. Herman, S. Emrani, H. Y. Figueroa, B. T. Hyman, P. Davies, K. E. Duff, 3d visualization of the temporal and spatial spread of tau pathology reveals extensive sites of tau accumulation associated with neuronal loss and recognition memory deficit in aged tau transgenic mice. PLOS ONE 11, e0159463 (2016). 27466814 PMC4965059
  8. [11]S. Wegmann, E. A. Maury, M. J. Kirk, L. Saqran, A. Roe, S. L. De Vos, S. Nicholls, Z. Fan, S. Takeda, O. Cagsal-Getkin, C. M. William, T. L. Spires-Jones, R. Pitstick, G. A. Carlson, A. M. Pooler, B. T. Hyman, Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity. EMBO J. 34, 3028– 3041 (2015). 26538322 PMC4687785
  9. [14]H. Braak, D. R. Thal, E. Ghebremedhin, K. D. Tredici, Stages of the pathologic process in Alzheimer disease: Age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960– 969 (2011). 22002422
  10. [15]T. E. Cope, T. Rittman, R. J. Borchert, P. S. Jones, D. Vatansever, K. Allinson, L. Passamonti, P. V. Rodriguez, W. R. Bevan-Jones, J. T. O’Brien, J. B. Rowe, Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy. Brain 141, 550– 567 (2018). 29293892 PMC5837359
  11. [17]S. I. A. Cohen, L. Rajah, C. H. Yoon, A. K. Buell, D. A. White, R. A. Sperling, M. Vendruscolo, E. M. Terentjev, C. M. Dobson, D. A. Weitz, T. P. J. Knowles, Spatial propagation of protein polymerization. Phys. Rev. Lett. 112, 098101 (2014). 24655282
  12. [18]J. Weickenmeier, E. Kuhl, A. Goriely, Multiphysics of prionlike diseases: Progression and atrophy. Phys. Rev. Lett. 121, 158101 (2018). 30362787
  13. [20]J. L. Furman, J. Vaquer-Alicea, C. L. White, N. J. Cairns, P. T. Nelson, M. I. Diamond, Widespread tau seeding activity at early braak stages. Acta Neuropathol. 133, 91– 100 (2017). 27878366 PMC5833300
  14. [23]J. Qian, B. T. Hyman, R. A. Betensky, Neurofibrillary tangle stage and the rate of progression of Alzheimer symptoms: Modeling using an autopsy cohort and application to clinical trial design. JAMA Neurol. 74, 540– 548 (2017). 28288263 PMC5547572
  15. [25]B. B. Holmes, J. L. Furman, T. E. Mahan, T. R. Yamasaki, H. Mirbaha, W. C. Eades, L. Belaygorod, N. J. Cairns, D. M. Holtzman, M. I. Diamond, Proteopathic tau seeding predicts tauopathy in vivo. Proc. Natl. Acad. Sci. U.S.A. 111, E4376– E4385 (2014). 25261551 PMC4205609
  16. [26]T. P. J. Knowles, C. A. Waudby, G. L. Devlin, S. I. A. Cohen, A. Aguzzi, M. Vendruscolo, E. M. Terentjev, M. E. Welland, C. M. Dobson, An analytical solution to the kinetics of breakable filament assembly. Science 326, 1533– 1537 (2009). 20007899
  17. [27]G. Meisl, T. Kurt, I. Condado-Morales, C. Bett, S. Sorce, M. Nuvolone, T. C. T. Michaels, D. Heinzer, M. Avar, S. I. A. Cohen, S. Hornemann, A. Aguzzi, C. M. Dobson, C. J. Sigurdson, T. P. J. Knowles, Scaling analysis reveals the mechanism and rates of prion replication in vivo. Nat. Struct. Mol. Biol. 28, 365– 372 (2021). 33767451 PMC8922999
  18. [28]F. Kundel, L. Hong, B. Falcon, W. A. McEwan, T. C. T. Michaels, G. Meisl, N. Esteras, A. Y. Abramov, T. J. P. Knowles, M. Goedert, D. Klenerman, Measurement of tau filament fragmentation provides insights into prion-like spreading. ACS Chem. Neurosci. 9, 1276– 1282 (2018). 29590529 PMC6014609
  19. [29]S. Wegmann, B. Eftekharzadeh, K. Tepper, K. M. Zoltowska, R. E. Bennett, S. Dujardin, P. R. Laskowski, D. M. Kenzie, T. Kamath, C. Commins, C. Vanderburg, A. D. Roe, Z. Fan, A. M. Molliex, A. Hernandez-Vega, D. Muller, A. A. Hyman, E. Mandelkow, J. P. Taylor, B. T. Hyman, Tau protein liquid–liquid phase separation can initiate tau aggregation. EMBO J. 37, e98049 (2018). 29472250 PMC5881631
  20. [30]L. D. Evans, T. Wassmer, G. Fraser, J. Smith, M. Perkinton, A. Billinton, F. J. Livesey, Extracellular monomeric and aggregated tau efficiently enter human neurons through overlapping but distinct pathways. Cell Rep. 22, 3612– 3624 (2018). 29590627 PMC5896171
  21. [31]W. A. McEwan, B. Falcon, M. Vaysburd, D. Clift, A. L. Oblak, B. Ghetti, M. Goedert, L. C. James, Cytosolic fc receptor trim21 inhibits seeded tau aggregation. Proc. Natl. Acad. Sci. U.S.A. 114, 574– 579 (2017). 28049840 PMC5255578
  22. [32]Z. Ahmed, J. Cooper, T. K. Murray, K. Garn, E. M. Naughton, H. Clarke, S. Parhizkar, M. A. Ward, A. Cavallini, S. Jackson, S. Bose, F. Clavaguera, M. Tolnay, I. Lavenir, M. Goedert, M. L. Hutton, M. J. O’Neill, A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: The pattern of spread is determined by connectivity, not proximity. Acta Neuropathol. 127, 667– 683 (2014). 24531916 PMC4252866
  23. [33]N. Franzmeier, J. Neitzel, A. Rubinski, R. Smith, O. Strandberg, R. Ossenkoppele, O. Hansson, M. Ewers; Alzheimer’s Disease Neuroimaging Initiative (ADNI), Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease. Nat. Commun. 11, 347 (2020). 31953405 PMC6969065
  24. [34]A. Aoyagi, C. Condello, J. Stöhr, W. Yue, B. M. Rivera, J. C. Lee, A. L. Woerman, G. Halliday, S. van Duinen, M. Ingelsson, L. Lannfelt, C. Graff, T. D. Bird, C. Dirk Keene, W. W. Seeley, W. F. De Grado, S. B. Prusiner, Aβ and tau prion-like activities decline with longevity in the Alzheimer’s disease human brain. Sci. Transl. Med. 11, eaat8462 (2019). 31043574 PMC6640844
  25. [35]J. L. Whitwell, P. Martin, J. Graff-Radford, M. M. Machulda, M. L. Senjem, C. G. Schwarz, S. D. Weigand, A. J. Spychalla, D. A. Drubach, C. R. Jack Jr., V. J. Lowe, K. A. Josephs, The role of age on tau pet uptake and gray matter atrophy in atypical Alzheimer’s disease. Alzheimers Dement. 15, 675– 685 (2019). 30853465 PMC6511453
  26. [36]A. Whittington, D. J. Sharp, R. N. Gunn, Spatiotemporal distribution of β-amyloid in Alzheimer disease is the result of heterogeneous regional carrying capacities. J. Nucl. Med. 59, 822– 827 (2018). 29146694 PMC5932528
  27. [37]G. Meisl, A. J. Dear, T. C. T. Michaels, T. P. J. Knowles, Mechanism, scaling and rates of protein aggregation from in vivo measurements. arXiv: 2008.09699 [physics.bio-ph] (21 August 2020). · arXiv
  28. [38]B. J. Hanseeuw, R. A. Betensky, H. I. L. Jacobs, A. P. Schultz, J. Sepulcre, J. Alex Becker, D. M. O. Cosio, M. Farrell, Y. T. Quiroz, E. C. Mormino, R. F. Buckley, K. V. Papp, R. A. Amariglio, I. Dewachter, A. Ivanoiu, W. Huijbers, T. Hedden, G. A. Marshall, J. P. Chhatwal, D. M. Rentz, R. A. Sperling, K. Johnson, Association of amyloid and tau with cognition in preclinical Alzheimer disease: A longitudinal study. JAMA Neurol. 76, 915– 924 (2019). 31157827 PMC6547132
  29. [39]J. C. Sang, G. Meisl, A. M. Thackray, L. Hong, A. Ponjavic, T. P. J. Knowles, R. Bujdoso, D. Klenerman, Direct observation of murine prion protein replication in vitro. J. Am. Chem. Soc. 140, 14789– 14798 (2018). 30351023 PMC6225343
  30. [40]G. Meisl, X. Yang, C. M. Dobson, S. Linse, T. P. J. Knowles, Modulation of electrostatic interactions to reveal a reaction network unifying the aggregation behaviour of the aβ42 peptide and its variants. Chem. Sci. 8, 4352– 4362 (2017). 28979758 PMC5580342
  31. [41]S. J. Jackson, C. Kerridge, J. Cooper, A. Cavallini, B. Falcon, C. V. Cella, A. Landi, P. G. Szekeres, T. K. Murray, Z. Ahmed, M. Goedert, M. Hutton, M. J. O’Neill, S. Bose, Short fibrils constitute the major species of seed-competent tau in the brains of mice transgenic for human p301s tau. J. Neurosci. 36, 762– 772 (2016). 26791207 PMC4719013

Cited by

Sorted by citations

Authors
Meisl, G., Hidari, E., Allinson, K., Rittman, T., DeVos, S. L., Sanchez, J. S., Xu, C. K., Duff, K. E., Johnson, K. A., Rowe, J. B., Hyman, B. T., Knowles, T. P. J., & Klenerman, D.
Affiliations
  • University of Cambridge (GB)
  • Harvard University (US)
  • University College London (GB)
  • MRC Cognition and Brain Sciences Unit (GB)
Corresponding author
  • Hyman, Bradley T.
  • Knowles, Tuomas P. J.
  • Klenerman, David
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2021-10-29
Volume
7
Issue
44
Pages
eabh1448-eabh1448
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.abh1448
PMC
PMC8555892
OpenAlex
W3208196021
Cited by
127
References
10
Citations by year
2026: 15 · 2025: 22 · 2024: 19 · 2023: 32 · 2022: 36 · 2021: 3
FWCI
14.14
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • Apollo (cc-by)
Funders
  • JPB Foundation
  • Wellcome Trust (103838/Z/14/Z, 103838, BRC-1215-20014)
  • Alzheimer's Society
  • National Institute for Health and Care Research ([IS-BRC-1215-20014, BRC1215-20014)
  • Royal Society (BRC-1215-20014)
  • Cambridge University Hospitals (146281)
  • UK Dementia Research Institute
  • National Institutes of Health
  • Medical Research Council (BRC-1215-20014, MR/M009041/1)
  • NIHR Cambridge Biomedical Research Centre ((BRC-1215-20014))
  • National Institute on Aging (RF1AG063521, RF1AG056151, RF1AG059789, P30AG062421)
  • H2020 European Research Council (669237)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, tau protein, rate-determining step, Braak staging, tau PET, neocortex, reaction kinetics, disease progression

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