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Cited by 359Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive tau PET in Alzheimer's disease

Open access
Mattsson-Carlgren, Niklas, Andersson, Emelie, Janelidze, Shorena, Ossenkoppele, Rik, Insel, Philip, Strandberg, Olof, Zetterberg, Henrik, Rosen, Howard J. +8 more·2020·Science Advances
DOI 10.1126/sciadv.aaz2387PMC PMC7159908
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Abstract

Aβ pathology may induce changes in soluble tau release and phosphorylation, which is later followed by tau aggregation.

AI snapshot

Written from the paper’s full text.

TL;DR

In the Swedish BioFINDER Tau PET substudy, Aβ deposition was associated with early increases in CSF soluble and phosphorylated tau, especially P-tau217, before Tau PET became positive. These soluble tau changes statistically mediated the relationship between Amyloid PET and Tau PET, suggesting a window before significant PHF-tau aggregation.

Key findings

  • Among 131 participants, Aβ+ CU had higher CSF P-tau181, P-tau217, and T-tau than Aβ− CU (P ≤ 0.0001) but did not differ on Tau PET measures. In Aβ+ CU, positivity was 70.0% for CSF P-tau217, 55.0% for P-tau181, 22.5% for T-tau, and only 2.5% for Tau PET ITC.
  • Isolated CSF P-tau positivity with negative Tau PET was common (28.2 to 51.1%), whereas isolated Tau PET positivity was rare (0.8 to 3.1%). In Tau PET–negative CU with an early CSF sample a median of 3.8 years before Tau PET, 56.3% of Aβ+ were positive for P-tau217, 25.0% for P-tau181, and 9.4% for T-tau; 0% of Aβ− CU were positive.
  • Aβ+ CU showed greater yearly increases than Aβ− CU in CSF P-tau217 [median 13.42 ng/liter/year (IQR, 4.94 to 22.12)], P-tau181 [7.06 (3.09 to 14.29)], and T-tau [10.65 (1.96 to 22.78)]. Spline thresholds showed CSF P-tau217 increased at 0.679 SUVR, P-tau181 at 0.684 SUVR, and T-tau at 0.695 SUVR, before the Amyloid PET positivity threshold of 0.743 SUVR; Tau PET increased at 0.772 SUVR (ITC) or 0.859 SUVR (Braak V–VI).
  • P-tau217 and P-tau181 mediated 82% and 68% of the Amyloid PET effect on Tau PET, respectively; T-tau mediated 41%. In 5xFAD mice, CSF T-tau increased at 4 months despite no tau aggregates, and 12 of 12 MAPT mutation carriers had normal CSF P-tau, with 10 of 12 normal CSF T-tau.

Methods

  • Prospective Swedish BioFINDER Tau PET substudy of 131 participants: 18 Aβ− CU, 40 Aβ+ CU, 38 Aβ+ with mild cognitive deficits (CDR 0.5), and 35 Aβ+ AD dementia (CDR 1 to 3), plus 12 MAPT mutation carriers. Measures included CSF T-tau, P-tau181, P-tau217, Tau368, 18F-flutemetamol Amyloid PET, 18F-flortaucipir Tau PET, MRI, and longitudinal subsets.
  • Main analyses used linear regression adjusted for age and sex, nonlinear spline models for continuous Amyloid PET thresholds, mediation analysis, and longitudinal models. Cut points were defined as mean plus two SDs in independent Aβ− CU cohorts. Mouse experiments used 5xFAD mice and nontransgenic littermates with CSF T-tau and Thioflavin S plaque quantification.

Limitations

  • Stated in the paper: lack of neuropathology to verify correlations between tau measures and brain changes; the longitudinal part was relatively small and differed between CSF and Tau PET measures; sensitivity may differ across techniques, and future studies are needed to compare CSF P-tau with interstitial fluid or brain tissue P-tau.
  • Evident from the text: the human findings are observational and do not prove causality; the 5xFAD mouse model does not develop tau aggregates and CSF P-tau could not be measured in mice; the cohort was drawn from a memory-clinic/BioFINDER setting, which may limit generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1126/sciadv.aaz2387

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 39 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Aβ+ individuals with mild cognitive deficits had higher levels of all CSF and PET tau measures compared with both Aβ− CU and Aβ+ CU.

    “Aβ+ individuals with mild cognitive deficits had higher levels of all CSF and PET tau measures, compared with both Aβ− CU (CSF, P < 0.0001; PET, P ≤ 0.0032) and Aβ+ CU (P < 0.0001).”
    Quote in the paperSubstantial claim
  • Findingown data

    All Aβ− CU were negative on all tau biomarkers, except one individual who was positive for CSF P-tau181 and P-tau217.

    “All Aβ− CU were negative on all tau biomarkers, except one individual who was positive for CSF P-tau181 and P-tau217.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In symptomatic disease stages, positivity was common for all tau biomarkers, 71 to 100% for all except Tau PET Braak V-VI, which had 32 to 66% positivity.

    “In symptomatic disease stages, positivity was common for all tau biomarkers (71 to 100% for all, except Tau PET Braak V–VI, which had 32 to 66% positivity in symptomatic disease stages).”
    Quote in the paperSubstantial claim
  • Findingown data

    The P-tau/T-tau ratios strongly mediated the effects of Amyloid PET on Tau PET with full mediation effects.

    “The ratios strongly mediated the effects of Amyloid PET on Tau PET (full mediation effects; fig. S6).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
    • Rests on an assumption: Tau PET represents PHF-tau.
  • Findingown data

    Most individuals were either concordant negative or positive for CSF P-tau and Tau PET measures.

    “Most individuals were either concordant negative (range, 22.1 to 29.0%) or positive (range, 25.2 to 48.9%) for CSF P-tau and Tau PET measures”
    Quote in the paperNot a substantial claim
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 20

  • May combine two claims.

    Findingown data

    For CSF tau biomarkers, percentages positive did not differ markedly between Aβ+ with milder cognitive deficits and dementia, but for Tau PET the proportion of positivity increased from milder cognitive deficits to dementia.

    “For CSF tau biomarkers, the percentages of positive individuals did not differ markedly between Aβ+ with milder cognitive deficits and dementia, but for Tau PET, the proportion of positivity increased from milder cognitive deficits to dementia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aβ+ CU had higher CSF P-tau181, P-tau217, and T-tau than Aβ− CU, but did not differ on Tau PET measures.

    “Aβ+ CU had higher CSF P-tau181, P-tau217, and T-tau than Aβ− CU (P ≤ 0.0001), but did not differ on any of the Tau PET measures.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aβ+ AD dementia had higher levels of all tau measures compared with all other groups, except there was no difference for CSF T-tau between Aβ+ with milder cognitive deficits or dementia.

    “Aβ+ AD dementia had higher levels of all tau measures compared with all other groups (CSF, P ≤ 0.035; Tau PET, P ≤ 0.0013), except that there was no difference for CSF T-tau between Aβ+ with milder cognitive deficits or dementia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A large group of Aβ+ CU were positive for CSF tau biomarkers, ranging from 22% for CSF T-tau to 70% for CSF P-tau217, but only one Aβ+ CU was positive for Tau PET in inferior temporal cortex.

    “A large group of Aβ+ CU were positive for CSF tau biomarkers (ranging from 22% for CSF T-tau to 70% for CSF P-tau217; Table 1), but only one Aβ+ CU was positive for Tau PET [in inferior temporal cortex (ITC)].”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tau PET measures increased at 18F-flutemetamol 0.772 SUVR in inferior temporal cortex or 0.859 SUVR in Braak V-VI.

    “Tau PET measures increased at 18F-flutemetamol 0.772 (ITC) or 0.859 SUVR (Braak V–VI; Fig. 3, D and E).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
    • Rests on an assumption: Tau PET represents PHF-tau.

  • May combine two claims.

    Findingown data

    CSF Tau368 levels were slightly increased in Aβ+ individuals with mild cognitive deficits or AD dementia, but not significantly increased in Aβ+ CU compared with Aβ− CU, and there were no clear correlations between Tau368 and Tau PET uptake.

    “In sum, CSF Tau368 levels were slightly increased in Aβ+ individuals with mild cognitive deficits or AD dementia, but Tau368 levels were not significantly increased in Aβ+ CU compared with Aβ− CU, and there were no clear correlations between Tau368 and Tau PET uptake (fig. S7, A to C).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Tau PET represents PHF-tau.

  • May combine two claims.

    Findingown data

    The P-tau/T-tau ratios increased over time in Aβ+ CU, and spline models indicated they started to increase before Amyloid PET became positive.

    “The ratios also increased over time in Aβ+ CU, and spline models indicated that they started to increase before Amyloid PET became positive (fig. S5).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.

  • May combine two claims.

    Findingown data

    When using T-tau instead, mediation was more modest at 41%, and Amyloid PET retained an independent association with Tau PET.

    “When using T-tau instead, the mediation was more modest (41% mediation), and Amyloid PET retained an independent association with Tau PET.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
    • Rests on an assumption: Tau PET represents PHF-tau.

  • May combine two claims.

    Findingown data

    All 12 MAPT mutation carriers had normal levels of CSF P-tau, and 10 of 12 had normal levels of CSF T-tau.

    “We confirmed this hypothesis in a set of 12 MAPT mutation carriers (eight with cognitive impairment and four CU controls), where all 12 had normal levels of CSF P-tau, and 10 of 12 had normal levels of CSF T-tau (fig. S1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The increase in Tau PET as a function of 18F-flutemetamol was only seen in individuals with high CSF P-tau levels, but not in individuals with low CSF P-tau.

    “Furthermore, the increase in Tau PET as a function of 18F-flutemetamol was only seen in individuals with high CSF P-tau levels, but not in individuals with low CSF P-tau (Fig. 3, H and I).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
    • Rests on an assumption: Tau PET represents PHF-tau.

  • May combine two claims.

    Findingown data

    CSF P-tau217, P-tau181, and T-tau started to increase at 18F-flutemetamol 0.679 SUVR, 0.684 SUVR, and 0.695 SUVR, respectively.

    “CSF P-tau217, P-tau181, and T-tau started to increase already at 18F-flutemetamol 0.679 SUVR [95% confidence interval (CI), 0.671 to 0.695], 0.684 SUVR (95% CI, 0.675 to 0.703), and 0.695 SUVR (95% CI, 0.682 to 0.721), respectively”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.

  • May combine two claims.

    Findingown data

    Isolated CSF P-tau positivity was seen in 28.2 to 51.1% of individuals, while isolated Tau PET positivity was very rare at 0.8 to 3.1%.

    “but isolated CSF P-tau positivity was also seen in several cases (28.2 to 51.1%). Isolated Tau PET positivity was very rare (0.8 to 3.1%).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among Aβ+ CU, 18 (56.3%) were positive for CSF P-tau217, 8 (25.0%) for CSF P-tau181, and 3 (9.4%) for CSF T-tau in the early sample.

    “Among the Aβ+ CU, 18 (56.3%) were positive for CSF P-tau217, 8 (25.0%) for CSF P-tau181, and 3 (9.4%) for CSF T-tau in the early sample.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    P-tau217/T-tau and P-tau181/T-tau ratios were changed in Aβ+ CU and were often positive in individuals with negative Tau PET; the opposite was only seen in one individual for P-tau181/T-tau.

    “These ratios were also changed in Aβ+ CU and were often positive in individuals with negative Tau PET (but the opposite, a positive Tau PET with a negative CSF P-tau/T-tau ratio, was only seen in one individual, for P-tau181/T-tau; fig. S4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In contrast to CSF tau, Tau PET increases occurred well into the phase of Amyloid PET positivity and only in individuals who also had increased CSF P-tau levels.

    “In contrast to CSF tau, Tau PET increases occurred well into the phase of Amyloid PET positivity and only in individuals who also had increased CSF P-tau levels.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
    • Rests on an assumption: Tau PET represents PHF-tau.

  • May combine two claims.

    Findingcitation

    In 5xFAD mice, CSF T-tau levels started to increase slightly after extracellular Aβ plaques start to accumulate, and then continued to increase as the Aβ pathology progressed, despite a lack of formation of PHF-tau in these mice.

    “CSF T-tau levels (we did not measure CSF P-tau since, to our knowledge, there is no assay available to measure P-tau in the CSF of mice) started to increase slightly after extracellular Aβ plaques start to accumulate, and then continued to increase as the Aβ pathology progressed, despite a lack of formation of PHF-tau in these mice (25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Oakley H., Cole S. L., Logan S., Maus E., Shao P., Craft J., Guillozet-Bongaarts A., Ohno M., Disterhoft J., Van Eldik L., Berry R., Vassar R., Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129– 10140 (2006). 17021169 PMC6674618 source

      Not checked in the free run.

    • Rests on an assumption: The 5xFAD mouse model recapitulates aspects of Aβ-induced tau changes relevant to human AD.

  • May combine two claims.

    Findingown data

    Tau PET, but not CSF tau, predicted longitudinal cognitive decline.

    “This is also in line with our findings that Tau PET, but not CSF tau, predicted longitudinal cognitive decline”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Baseline CSF tau, but not baseline Tau PET, predicted future increases in Tau PET in people with cognitive impairment.

    “Furthermore, baseline CSF tau (but not baseline Tau PET) predicted future increases in Tau PET in people with cognitive impairment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tau PET represents PHF-tau.

  • May combine two claims.

    Findingown data

    P-tau (especially P-tau217) more strongly mediated the effect of Amyloid PET on Tau PET and was more clearly altered in the earliest stages of the disease than T-tau.

    “Although changes in T-tau were also seen early, P-tau (especially P-tau217) more strongly mediated the effect of Amyloid PET on Tau PET and was more clearly altered in the earliest stages of the disease (in Aβ+ CU several years before a negative Tau PET scan).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Correlations between in vivo CSF tau biomarkers and tau aggregates in postmortem tissue are weaker.

    “but correlations between in vivo CSF tau biomarkers and tau aggregates in postmortem tissue are weaker (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Buerger K., Ewers M., Pirttila T., Zinkowski R., Alafuzoff I., Teipel S. J., DeBernardis J., Kerkman D., McCulloch C., Soininen H., Hampel H., CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer’s disease. Brain 129, 3035– 3041 (2006). 17012293 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cell and animal experiments have verified that Aβ may induce pathologically relevant alterations in neuronal tau, including increased phosphorylation and release of tau.

    “Cell and animal experiments have verified that Aβ may induce pathologically relevant alterations in neuronal tau, including increased phosphorylation and release of tau (4, 5).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Stancu I.-C., Vasconcelos B., Terwel D., Dewachter I., Models of β-amyloid induced Tau-pathology: The long and “folded” road to understand the mechanism. Mol. Neurodegener. 9, 51 (2014). 25407337 PMC4255655 source

      Not checked in the free run.

    • cites [5] Maia L. F., Kaeser S. A., Reichwald J., Hruscha M., Martus P., Staufenbiel M., Jucker M., Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci. Transl. Med. 5, 194re2 (2013). 23863834 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Accumulation of Aβ fibrils is an initiating factor in AD and necessary for the formation of tau aggregates.

    “Accumulation of Aβ fibrils is thought to be an initiating factor in AD and necessary for the formation of tau aggregates (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Goedert M., Tau filaments in neurodegenerative diseases. FEBS Lett. 592, 2383– 2391 (2018). 29790176 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Neuropathological studies have shown that Tau PET correlates strongly to NFT and neuropil threads in the brain.

    “Neuropathological studies have shown that Tau PET correlates strongly to NFT and neuropil threads in the brain (10)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Smith R., Wibom M., Pawlik D., Englund E., Hansson O., Correlation of in vivo [18F]Flortaucipir with postmortem alzheimer disease tau pathology. JAMA Neurol. 76, 310– 317 (2018). PMC6439731 30508025 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Cognitive measures and atrophy are more strongly related to Tau PET than to CSF tau biomarkers.

    “Cognitive measures (15, 16) and atrophy (15) are more strongly related to Tau PET than to CSF tau biomarkers.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Mattsson N., Schöll M., Strandberg O., Smith R., Palmqvist S., Insel P. S., Hägerström D., Ohlsson T., Zetterberg H., Jögi J., Blennow K., Hansson O., 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol. Med. 9, 1212– 1223 (2017). 28743782 PMC5582410 source

      Not checked in the free run.

    • cites [16] La Joie R., Bejanin A., Fagan A. M., Ayakta N., Baker S. L., Bourakova V., Boxer A. L., Cha J., Karydas A., Jerome G., Maass A., Mensing A., Miller Z. A., O’Neil J. P., Pham J., Rosen H. J., Tsai R., Visani A. V., Miller B. L., Jagust W. J., Rabinovici G. D., Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90, e282– e290 (2018). 29282337 PMC5798657

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Transgenic animal experiments have shown that Aβ aggregates are associated with increased levels of soluble tau and increased tau phosphorylation.

    “For example, transgenic animal experiments have shown that Aβ aggregates are associated with increased levels of soluble tau and increased tau phosphorylation (5, 6).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Maia L. F., Kaeser S. A., Reichwald J., Hruscha M., Martus P., Staufenbiel M., Jucker M., Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci. Transl. Med. 5, 194re2 (2013). 23863834 source

      Not checked in the free run.

    • cites [6] Jin M., Shepardson N., Yang T., Chen G., Walsh D., Selkoe D. J., Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl. Acad. Sci. U.S.A. 108, 5819– 5824 (2011). 21421841 PMC3078381

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CSF tau biomarkers and Tau PET reflect different aspects of tau pathology and may become abnormal at different stages of the disease.

    “These previous studies suggest that CSF tau biomarkers and Tau PET reflect different aspects of tau pathology and may become abnormal at different stages of the disease.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [12] Brier M. R., Gordon B., Friedrichsen K., McCarthy J., Stern A., Christensen J., Owen C., Aldea P., Su Y., Hassenstab J., Cairns N. J., Holtzman D. M., Fagan A. M., Morris J. C., Benzinger T. L. S., Ances B. M., Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci. Transl. Med. 8, 338ra66 (2016). PMC5267531 27169802 source

      Not checked in the free run.

    • cites [13] Chhatwal J. P., Schultz A. P., Marshall G. A., Boot B., Gomez-Isla T., Dumurgier J., LaPoint M., Scherzer C., Roe A. D., Hyman B. T., Sperling R. A., Johnson K. A., Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly. Neurology 87, 920– 926 (2016). 27473132 PMC5035159 source

      Not checked in the free run.

    • cites [14] Gordon B. A., Friedrichsen K., Brier M., Blazey T., Su Y., Christensen J., Aldea P., McConathy J., Holtzman D. M., Cairns N. J., Morris J. C., Fagan A. M., Ances B. M., Benzinger T. L. S., The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging. Brain 139, 2249– 2260 (2016). 27286736 PMC4958902

      Not checked in the free run.

    • cites [15] Mattsson N., Schöll M., Strandberg O., Smith R., Palmqvist S., Insel P. S., Hägerström D., Ohlsson T., Zetterberg H., Jögi J., Blennow K., Hansson O., 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol. Med. 9, 1212– 1223 (2017). 28743782 PMC5582410 source

      Not checked in the free run.

    • cites [16] La Joie R., Bejanin A., Fagan A. M., Ayakta N., Baker S. L., Bourakova V., Boxer A. L., Cha J., Karydas A., Jerome G., Maass A., Mensing A., Miller Z. A., O’Neil J. P., Pham J., Rosen H. J., Tsai R., Visani A. V., Miller B. L., Jagust W. J., Rabinovici G. D., Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90, e282– e290 (2018). 29282337 PMC5798657

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    CSF tau protein levels and phosphorylation are increased already in Aβ+ CU, in up to 70% of individuals for CSF P-tau217, at a stage when insoluble PHF-tau deposition is rarely detected on Tau PET.

    “These results demonstrate that CSF tau protein levels and phosphorylation are increased already in Aβ+ CU (in up to 70% of individuals for CSF P-tau217), a stage of the disease when insoluble PHF-tau deposition is rarely detected on Tau PET.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Studies comparing CSF tau biomarkers with Tau PET have found that they are only moderately correlated, with the strongest correlations in symptomatic stages of AD and no or weak correlations in cognitively unimpaired individuals.

    “Studies comparing CSF tau biomarkers with Tau PET have found that they are only moderately correlated, with the strongest correlations in symptomatic stages of AD, and no or weak correlations in cognitively unimpaired (CU) individuals (12–16).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [12] Brier M. R., Gordon B., Friedrichsen K., McCarthy J., Stern A., Christensen J., Owen C., Aldea P., Su Y., Hassenstab J., Cairns N. J., Holtzman D. M., Fagan A. M., Morris J. C., Benzinger T. L. S., Ances B. M., Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci. Transl. Med. 8, 338ra66 (2016). PMC5267531 27169802 source

      Not checked in the free run.

    • cites [13] Chhatwal J. P., Schultz A. P., Marshall G. A., Boot B., Gomez-Isla T., Dumurgier J., LaPoint M., Scherzer C., Roe A. D., Hyman B. T., Sperling R. A., Johnson K. A., Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly. Neurology 87, 920– 926 (2016). 27473132 PMC5035159 source

      Not checked in the free run.

    • cites [14] Gordon B. A., Friedrichsen K., Brier M., Blazey T., Su Y., Christensen J., Aldea P., McConathy J., Holtzman D. M., Cairns N. J., Morris J. C., Fagan A. M., Ances B. M., Benzinger T. L. S., The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging. Brain 139, 2249– 2260 (2016). 27286736 PMC4958902

      Not checked in the free run.

    • cites [15] Mattsson N., Schöll M., Strandberg O., Smith R., Palmqvist S., Insel P. S., Hägerström D., Ohlsson T., Zetterberg H., Jögi J., Blennow K., Hansson O., 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol. Med. 9, 1212– 1223 (2017). 28743782 PMC5582410 source

      Not checked in the free run.

    • cites [16] La Joie R., Bejanin A., Fagan A. M., Ayakta N., Baker S. L., Bourakova V., Boxer A. L., Cha J., Karydas A., Jerome G., Maass A., Mensing A., Miller Z. A., O’Neil J. P., Pham J., Rosen H. J., Tsai R., Visani A. V., Miller B. L., Jagust W. J., Rabinovici G. D., Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90, e282– e290 (2018). 29282337 PMC5798657

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In AD, tau becomes truncated and hyperphosphorylated, which can increase the risk for tau to aggregate into paired helical filaments found in neurofibrillary tangles and neuropil threads.

    “In AD, tau becomes truncated and hyperphosphorylated (3), which can increase the risk for tau to aggregate into the paired helical filaments (PHF) that are found in neurofibrillary tangles (NFT) and neuropil treads in the brains of patients with AD (1).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Cicognola C., Brinkmalm G., Wahlgren J., Portelius E., Gobom J., Cullen N. C., Hansson O., Parnetti L., Constantinescu R., Wildsmith K., Chen H.-H., Beach T. G., Lashley T., Zetterberg H., Blennow K., Höglund K., Novel tau fragments in cerebrospinal fluid: Relation to tangle pathology and cognitive decline in Alzheimer’s disease. Acta Neuropathol. 137, 279– 296 (2019). 30547227 PMC6514201 source

      Not checked in the free run.

    • cites [1] Goedert M., Tau filaments in neurodegenerative diseases. FEBS Lett. 592, 2383– 2391 (2018). 29790176 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    P-tau217/T-tau and P-tau181/T-tau ratios increase before Tau PET and may link Aβ pathology to deposition of PHF-tau.

    “Together, these results show that the P-tau217/T-tau and P-tau181/T-tau ratios increase before Tau PET and may link Aβ pathology to deposition of PHF-tau.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
    • Rests on an assumption: Tau PET represents PHF-tau.

  • May combine two claims.

    Interpretationown data

    CSF tau levels increase in the presence of Aβ, but do not directly reflect an injury process leading to cognitive decline.

    “In contrast, CSF tau levels increase in the presence of Aβ, but do not directly reflect an injury process leading to cognitive decline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Aβ pathology leads to increased neuronal phosphorylation and release of tau, which seems necessary for the formation of tau deposits.

    “This suggests that Aβ pathology leads to increased neuronal phosphorylation and release of tau, which seems necessary for the formation of tau deposits.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD transgenic mouse model's CSF tau changes in response to Aβ pathology are informative about the human relationship between Aβ pathology and soluble tau.
    • Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
    • Rests on an assumption: Tau PET represents PHF-tau.

  • May combine two claims.

    Interpretationown data

    Early Aβ pathology is associated with marked changes in levels and phosphorylation of tau before deposition of PHF-tau is detected with Tau PET imaging, and changes in soluble tau mediate the effects of Aβ pathology on downstream deposition of tau aggregates.

    “To our knowledge, this is the first study to demonstrate directly in humans that early Aβ pathology is associated with marked changes in levels and phosphorylation of tau, before deposition of PHF-tau is detected with Tau PET imaging, and that changes in soluble tau mediate the effects of Aβ pathology on downstream deposition of tau aggregates.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
    • Rests on an assumption: Tau PET represents PHF-tau.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Slope differences were tested in linear regression models adjusted for age, sex, and time span between the two lumbar punctures.

    “Slope differences were tested in linear regression models, adjusted for age, sex, and time span between the two lumbar punctures.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    CSF P-tau markers, especially P-tau217, not only start to increase but also reach clearly abnormal levels several years before PHF-tau deposition can be detected by Tau PET.

    “These results show that CSF P-tau markers (especially P-tau217) not only start to increase but also, in many cases, reach clearly abnormal levels several years before PHF-tau deposition can be detected by Tau PET.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Increased release and phosphorylation of tau occur in response to fibrillar Aβ deposition, and these alterations link accumulation of Aβ plaques to deposition of PHF-tau as seen by Tau PET in humans, with a delay of several years after the first changes in soluble tau.

    “This study presents converging results from human individuals in asymptomatic and symptomatic stages of AD, and from an AD mouse model (5xFAD) that increased release and phosphorylation of tau occur in response to fibrillar Aβ deposition, and that these alterations in tau metabolism link the accumulation of Aβ plaques to deposition of PHF-tau as seen by Tau PET in humans, but with a delay of”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5xFAD transgenic mouse model's CSF tau changes in response to Aβ pathology are informative about the human relationship between Aβ pathology and soluble tau.
    • Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
    • Rests on an assumption: Tau PET represents PHF-tau.

  • May combine two claims.

    Interpretationreasoning

    Aβ pathology induces a change in brain metabolism of tau, including increased release and phosphorylation of tau at amino acid residues 217 and 181, where phosphorylation at position 217 may be a more pronounced early change, which later leads to accumulation of tau aggregates.

    “Together, these results support a model where Aβ pathology induces a change in brain metabolism of tau, including increased release and phosphorylation of tau at amino acid residues 217 and 181, where phosphorylation at position 217 may be a more pronounced early change, which later leads to accumulation of tau aggregates.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CSF concentrations of tau proteins reflect tau metabolism in the brain.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recent mass spectrometry-based study found increased degree of phosphorylation at position 217 compared with position 181 in CSF from patients with AD.

    “a recent mass spectrometry–based study found increased degree of phosphorylation at position 217 compared with position 181 in CSF from patients with AD (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Barthélemy N. R., Mallipeddi N., Moiseyev P., Sato C., Bateman R. J., Tau phosphorylation rates measured by mass spectrometry differ in the intracellular brain vs. extracellular cerebrospinal fluid compartments and are differentially affected by alzheimer’s disease. Front. Aging Neurosci. 11, 121 (2019). 31178717 PMC6537657 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    In humans with sporadic AD, metabolism of soluble tau is altered in the presence of Aβ and foreshadows significant tau deposition by several years.

    “These findings strengthen the amyloid cascade hypothesis and demonstrate in humans with sporadic (non–autosomal dominant) forms of AD that metabolism of soluble tau is altered in the presence of Aβ, and that this foreshadows significant tau deposition by several years.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
    • Rests on an assumption: Tau PET represents PHF-tau.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The ATN framework suggests that Tau PET and CSF P-tau can be used to define tau pathology ("T"), while CSF T-tau can be used to define neurodegeneration ("N") in AD.

    “A recently presented framework for AD research (the “ATN” framework) has suggested that Tau PET and CSF P-tau can be used to define tau pathology (“T”), while CSF T-tau can be used to define neurodegeneration (“N”) in AD (18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Jack C. R. Jr., Bennett D. A., Blennow K., Carrillo M. C., Dunn B., Haeberlein S. B., Holtzman D. M., Jagust W., Jessen F., Karlawish J., Liu E., Molinuevo J. L., Montine T., Phelps C., Rankin K. P., Rowe C. C., Scheltens P., Siemers E., Snyder H. M., Sperling R., Contributors, NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14, 535– 562 (2018). 29653606 PMC5958625 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    CSF P-tau217 and P-tau181 may be increased very early (in preclinical stages) and then reach a plateau; in very late stages, perhaps even a decrease.

    “not only CSF P-tau217 but also P-tau181 may be increased very early (in preclinical stages) and then reach a plateau [and in very late stages, perhaps even a decrease, as has also been suggested by findings from autosomal dominant AD (35)].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] McDade E., Wang G., Gordon B. A., Hassenstab J., Benzinger T. L. S., Buckles V., Fagan A. M., Holtzman D. M., Cairns N. J., Goate A. M., Marcus D. S., Morris J. C., Paumier K., Xiong C., Allegri R., Berman S. B., Klunk W., Noble J., Ringman J., Ghetti B., Farlow M., Sperling R. A., Chhatwal J., Salloway S., Graff-Radford N. R., Schofield P. R., Masters C., Rossor M. N., Fox N. C., Levin J., Jucker M., Bateman R. J.; Dominantly inherited alzheimer network, Longitudinal cognitive and biomarker changes in dominantly inherited alzheimer disease. Neurology 91, e1295– e1306 (2018). 30217935 PMC61772 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau PET may continue to increase throughout the disease course, which gives it a very high diagnostic accuracy during the later stage of the disease.

    “Tau PET may continue to increase throughout the disease course, which gives it a very high diagnostic accuracy during the later stage of the disease (36).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Ossenkoppele R., Rabinovici G. D., Smith R., Cho H., Schöll M., Strandberg O., Palmqvist S., Mattsson N., Janelidze S., Santillo A., Ohlsson T., Jögi J., Tsai R., La Joie R., Kramer J., Boxer A. L., Gorno-Tempini M. L., Miller B. L., Choi J. Y., Ryu Y. H., Lyoo C. H., Hansson O., Discriminative accuracy of [18F]flortaucipir positron emission tomography for alzheimer disease vs other neurodegenerative disorders. JAMA 320, 1151– 1162 (2018). 30326496 PMC6233630 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The first tau deposits initiated by Aβ may occur in dystrophic neurites surrounding the Aβ plaques, with the formation of widespread tangle pathology coming later, potentially spreading through functionally connected neurons.

    “The first tau deposits that are initiated by Aβ may occur in dystrophic neurites surrounding the Aβ plaques, with the formation of widespread tangle pathology coming later (29), potentially spreading through functionally connected neurons.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] He Z., Guo J. L., McBride J. D., Narasimhan S., Kim H., Changolkar L., Zhang B., Gathagan R. J., Yue C., Dengler C., Stieber A., Nitla M., Coulter D. A., Abel T., Brunden K. R., Trojanowski J. Q., Lee V. M.-Y., Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29– 38 (2018). 29200205 PMC5760353 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Comparisons of in vivo Tau PET versus neuropathology data have shown good correlations between Tau PET signal and tau neuropathology quantifications, although individuals in those studies had substantial tau accumulation.

    “comparisons of in vivo Tau PET versus neuropathology data have shown good correlations between Tau PET signal and tau neuropathology quantifications, although we note that individuals in those studies had substantial tau accumulation (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Smith R., Wibom M., Pawlik D., Englund E., Hansson O., Correlation of in vivo [18F]Flortaucipir with postmortem alzheimer disease tau pathology. JAMA Neurol. 76, 310– 317 (2018). PMC6439731 30508025 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Changes in CSF P-tau217 and P-tau181 indicate "disease state," i.e., the presence of a pathological process associated with AD from very early on in the disease, while the continuous increase in Tau PET makes Tau PET a marker of "disease stage" throughout the symptomatic phases of AD.

    “changes in CSF P-tau217 and P-tau181 would indicate “disease state,” i.e., the presence of a pathological process associated with AD from very early on in the disease, while the continuous increase in Tau PET [and the strong correlations between Tau PET and atrophy and cognitive decline; (39)] would make Tau PET a marker of “disease stage” throughout the symptomatic phases of AD.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [38] Blennow K., Hampel H., CSF markers for incipient Alzheimer’s disease. Lancet Neurol. 2, 605– 613 (2003). 14505582 source

      Not checked in the free run.

    • cites [39] Mattsson N., Insel P. S., Donohue M., Jögi J., Ossenkoppele R., Olsson T., Schöll M., Smith R., Hansson O., Predicting diagnosis and cognition with 18F-AV-1451 tau PET and structural MRI in Alzheimer’s disease. Alzheimers Dement. 15, 570– 580 (2019). 30639421 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    T-tau levels may be increased also in other conditions with brain injury without tau aggregation.

    “T-tau levels may be increased also in other conditions with brain injury without tau aggregation (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Hesse C., Rosengren L., Vanmechelen E., Vanderstichele H., Jensen C., Davidsson P., Blennow K., Cerebrospinal fluid markers for Alzheimer’s disease evaluated after acute ischemic stroke. J. Alzheimers Dis. 2, 199– 206 (2000). 12214084

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The change in soluble tau metabolism (including hyperphosphorylation) is a link between the accumulation of Aβ and the widespread deposition of insoluble tau aggregates detectable by Tau PET imaging, with the latter following several years after detection of the first changes in soluble tau.

    “The change in soluble tau metabolism (including hyperphosphorylation) is a link between the accumulation of Aβ and the widespread deposition of insoluble tau aggregates detectable by Tau PET imaging, with the latter following several years after detection of the first changes in soluble tau.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CSF concentrations of tau proteins reflect tau metabolism in the brain.
    • Rests on an assumption: Aβ status defined by the CSF Aβ42/Aβ40 ratio reflects brain Aβ pathology.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Lack of neuropathology to verify the correlations between the different tau measures and neuropathological changes in the brain is a limitation of the study.

    “Limitations of the study include the lack of neuropathology to verify the correlations between the different tau measures and neuropathological changes in the brain.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The longitudinal part of the study was relatively small and differed between CSF and Tau PET measures.

    “Another limitation was that the longitudinal part of the study was relatively small and differed between CSF and Tau PET measures.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The CSF Aβ42/Aβ40 ratio was used to define Aβ status, with a previously defined cut point (<0.1) to define positivity.

    “The CSF Aβ42/Aβ40 ratio (using EUROIMMUN data) was used to define Aβ status, with a previously defined cut point (<0.1) to define positivity (42).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Janelidze S., Zetterberg H., Mattsson N., Palmqvist S., Vanderstichele H., Lindberg O., van Westen D., Stomrud E., Minthon L., Blennow K.; Swedish BioFINDER study group, Hansson O., CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: Better diagnostic markers of Alzheimer disease. Ann. Clin. Transl. Neurol. 3, 154– 165 (2016). 27042676 PMC4774260 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Aβ aggregation leads to both increased tau release and phosphorylation, but it is primarily the altered tau hyperphosphorylation that is associated with the deposition of tau aggregates in humans.

    “Our results therefore support that Aβ aggregation leads to both increased tau release (as shown in both the human individuals and the mouse model data) and phosphorylation, but it is primarily the altered tau hyperphosphorylation that is associated with the deposition of tau aggregates in humans.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    A cut point for Amyloid PET global uptake was defined in a cohort of 428 BioFINDER participants using mixture modeling analysis.

    “A cut point for this global uptake was defined in a cohort of 428 BioFINDER participants using mixture modeling analysis as described elsewhere (SUVR 0.743; Mattsson, Leuzy et al., in press, Neurology).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Analyses were done using a priori defined ROIs.

    “Analyses were done using a priori defined ROIs.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All regression models were adjusted for age, sex, and (when appropriate) the time-lag between lumbar puncture and Tau PET scan.

    “All regression models were adjusted for age, sex, and (when appropriate) the time-lag between lumbar puncture and Tau PET scan.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Cut points for tau biomarkers were defined based on the mean levels plus two SDs of the respective biomarker in independent cohorts of Aβ− CU.

    “We defined cut points for tau biomarkers based on the mean levels plus two SDs of the respective biomarker in independent cohorts of Aβ− CU.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Post hoc analysis for group comparisons between the youngest group and all other groups was corrected for multiple comparisons using the Bonferroni method.

    “Post hoc analysis for group comparisons between the youngest group and all other groups was performed using the Mann-Whitney U test, and corrected for multiple comparisons using the Bonferroni method.”
    Quote in the paperNot a substantial claim
56 of 56

  • The paper relies on this without support.

    Only limited data exist from humans on the temporal relationships between development of Aβ plaques and altered release, phosphorylation, and aggregation of tau.

    “but only limited data exist from humans on the temporal relationships between development of Aβ plaques and altered release, phosphorylation, and aggregation of tau.”

  • The paper relies on this without support.

    The 5xFAD transgenic mouse model's CSF tau changes in response to Aβ pathology are informative about the human relationship between Aβ pathology and soluble tau.

    “To corroborate the findings from humans, we studied changes in CSF tau in a transgenic mice model of AD (5xFAD).”

  • The paper relies on this without support.

    Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.

    “continuous 18F-flutemetamol (Amyloid) PET (representing Aβ fibrillar plaque load; Fig. 3)”

  • The paper relies on this without support.

    Tau PET represents PHF-tau.

    “Tau PET (representing PHF-tau)”

  • The paper relies on this without support.

    CSF concentrations of tau proteins reflect tau metabolism in the brain.

    “To conclude, the CSF levels of tau proteins, especially P-tau217 and P-tau181, are increased in response to Aβ deposition in humans in early stages of AD.”

  • The paper relies on this without support.

    The 5xFAD mouse model recapitulates aspects of Aβ-induced tau changes relevant to human AD.

    “Some of the findings from humans could be translated back to 5xFAD mice”

  • The paper relies on this without support.

    Aβ status defined by the CSF Aβ42/Aβ40 ratio reflects brain Aβ pathology.

    “The CSF Aβ42/Aβ40 ratio (using EUROIMMUN data) was used to define Aβ status, with a previously defined cut point (<0.1) to define positivity (42).”
7 of 7

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?

  • Increases in CSF p-tau occur before both tau PET and established measures of neuronal death, so CSF p-tau cannot merely reflect NFT leakage from dying neurons.

    “Increases in CSF p-tau occur before both tau PET20,63,64 and established measures of neuronal death (e.g., neurofilament light, magnetic resonance imaging or [18F]FDG PET), thus CSF p-tau cannot merely reflect NFT leakage from dying neurons.”

    From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [63]

  • Current in-vivo detection of tau positivity using 18F-flortaucipir PET seems to correspond only to widespread tau pathology (Braak stages ≥IV), whereas CSF phosphorylated tau elevation can reflect earlier stages of tauopathy.

    “The current in-vivo detection of tau positivity using 18F-flortaucipir PET seems to correspond only to widespread tau pathology in the brain (ie, Braak stages ≥IV),69 whereas CSF phosphorylated tau elevation can reflect earlier stages of tauopathy.70”

    From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [70]

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • Longitudinal CSF statistical comparison is cited as Fig. 3 instead of Fig. 2

    Minor

    The text directs readers to Fig. 3 for the adjusted comparison of longitudinal CSF tau changes, but the Fig. 2 caption reports that comparison. Fig. 3 instead concerns tau measures in relation to Amyloid PET load.

  • Mouse CSF tau increase is cited to the wrong Fig. 5 panel

    Minor

    The text cites Fig. 5A for the increase in CSF tau at 4 months, but the figure caption identifies panel A as plaque staining and panel B as the CSF T-tau measurements.

2 of 2

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Authors
Mattsson-Carlgren, N., Andersson, E., Janelidze, S., Ossenkoppele, R., Insel, P., Strandberg, O., Zetterberg, H., Rosen, H. J., Rabinovici, G., Chai, X., Blennow, K., Dage, J. L., Stomrud, E., Smith, R., Palmqvist, S., & Hansson, O.
Affiliations
  • Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.
  • Lund University (SE)
  • Sahlgrenska University Hospital (SE)
  • University of California, San Francisco (US)
  • Eli Lilly (United States) (US)
Corresponding author
Hansson, Oskar
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2020-04-17
Volume
6
Issue
16
Pages
eaaz2387-eaaz2387
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.aaz2387
PMC
PMC7159908
OpenAlex
W3016877536
Semantic Scholar
474138087e67e9eaed4ae5baf6485f7c164d79cc
Cited by
359
References
48
Citations by year
2026: 43 · 2025: 64 · 2024: 64 · 2023: 55 · 2022: 55 · 2021: 54 · 2020: 23
FWCI
28.11
Type
journal article
Language
en
Open access
Locations
  • Science Advances (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, cc-by)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • Parkinson Research Foundation
  • H2020 European Research Council
  • Swedish Research Council Formas
  • Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
  • Region Skåne
  • Marianne and Marcus Wallenberg Foundation
  • Swedish Brain Foundation
  • Swedish Alzheimer Foundation
  • the Knut and Alice Wallenberg Foundation
  • Medical Faculty at Lund University
  • Strategic Research Area MultiPark
  • Swedish Medical Association
  • Skåne University Hospital Foundation
  • Parkinson foundation of Sweden
  • Torsten Söderberg Foundation
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, amyloid-beta deposition, tau phosphorylation, soluble tau, tau PET, cerebrospinal fluid biomarkers, tau aggregation, 5xFAD mice, amyloid-beta aggregation
MeSH terms
Alzheimer Disease, Animals, Phosphorylation, Biomarkers, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography, Mice

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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