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Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease
Open accessAbstract
SUMMARY To elucidate the role of Tau isoforms and post-translational modification (PTM) stoichiometry in Alzheimer’s disease (AD), we generated a high-resolution quantitative proteomics map of 95 PTMs on multiple isoforms of Tau isolated from postmortem human tissue from 49 AD and 42 control subjects. Although Tau PTM maps reveal heterogeneity across subjects, a subset of PTMs display high occupancy and frequency for AD, suggesting importance in disease. Unsupervised analyses indicate that PTMs occur in an ordered manner, leading to Tau aggregation. The processive addition and minimal set of PTMs associated with seeding activity was further defined by analysis of size-fractionated Tau. To summarize, features in the Tau protein critical for disease intervention at different stages of disease are identified, including enrichment of 0N and 4R isoforms, underrepresentation of the C terminus, an increase in negative charge in the proline-rich region (PRR), and a decrease in positive charge in the microtubule binding domain (MBD).
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TL;DR
This study used quantitative mass spectrometry to map tau post-translational modifications in postmortem brain from Alzheimer’s disease and control donors, finding heterogeneous but ordered modification patterns that track disease stage. It identifies isoform shifts and charge-related modifications linked to aggregation and seeding.
Key findings
Across 49 AD and 42 control subjects, 95 PTMs at 88 residues were mapped, including 55 phosphorylation, 17 ubiquitination, 19 acetylation, and 4 methylation sites; insoluble tau was about 100-fold higher in AD (~1,000 vs ~10 fmol/mg), while soluble tau was lower (~3,000 vs ~5,000 fmol/mg). Insoluble AD tau was enriched for 0N and 4R isoforms; N-terminal and C-terminal regions were underrepresented, proline-rich region phosphorylation was high, and microtubule-binding-domain acetylation/ubiquitination increased with aggregate size. Unsupervised clustering separated subjects into groups reflecting Braak stage and PTM burden, and a classifier trained on cohort 1 predicted AD pathology in cohort 2 with >0.92 accuracy. Size-fractionated tau showed seeding-competent high-molecular-weight/insoluble species had microtubule-binding-domain modifications and 20 phosphosites in the high-molecular-weight fraction, while seeding-incompetent low-molecular-weight/soluble species were N-terminally enriched and had fewer proline-rich-region phosphosites.
Methods
Postmortem BA39 angular gyrus from 49 AD and 42 matched controls was analyzed, plus BA46 frontal gyrus in 9 controls and 10 AD subjects; high- and low-molecular-weight tau fractions came from 4 AD and 4 control subjects. FLEXITau targeted mass spectrometry quantified absolute tau and isoform-specific peptides, while data-dependent LC-MS/MS mapped PTMs; sarkosyl solubility and size-exclusion/MC1 fractionation separated tau species. Analyses included PCA, hierarchical clustering, PLS-DA, Spearman correlation, and a stochastic gradient descent classifier; data were deposited in ProteomeXchange.
Limitations
Stated: using top-ranked PTMs as biomarkers requires an adequately powered study with suitable specimens, and high-molecular-weight fraction PTM patterns showed patient-to-patient variability. Stated/evident: the postmortem cross-sectional design cannot directly prove temporal order or causality of PTM progression, and some controls had early AD-like PTMs, complicating group boundaries. Evident: some analyses rely on small subsets (BA46 n=19; high-/low-molecular-weight n=8), and stoichiometry for some microtubule-binding-domain sites was around 50%, so not every tau molecule carries those modifications.
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96 Own result · 35 Own interpretation · 19 Not checked yet · 14 Own method · 2 No basis given
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“Our analysis extended this to 55 phosphorylation sites on pathological insoluble Tau in BA39 and 43 phosphosites in B46 (Figure S2C).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“The median concentrations of pathological insoluble Tau in BA39 were 100-fold higher in AD (~1,000 fmol/mg fresh weight of tissue) compared with controls (~10 fmol/mg fresh weight of tissue) (Figure 1B).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Concentrations and Isoform Distributions in AD and Control Subjects
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“Interestingly, in soluble Tau, the most abundant species are the 1N and 4R isoforms”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Concentrations and Isoform Distributions in AD and Control Subjects
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“underrepresentation of the C terminus”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > Abstract
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“The data and subsequent analyses showed that that the highest-frequency PTMs, isoform distributions, and quantitative profiles of the BA46 region are shared between the two brain regions”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS
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“subjects in these clusters have a significantly higher Tau and amyloid burden in BA39 than subjects falling into clusters a and d (Figure 2B).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“Increased phosphorylation of the PRR is also observed in symptomatic patients in cluster d as well as in AD clusters b and c”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“Although Tau PTM maps reveal heterogeneity across subjects”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > Abstract
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“The total amount of soluble Tau is lower in AD patients (~3,000 fmol/mg fresh weight of tissue) compared with control subjects (~5,000 fmol/mg fresh weight of tissue) (Figure 1B).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Concentrations and Isoform Distributions in AD and Control Subjects
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“In particular, the peptides spanning [195–209] and [212–224] that encompass the sites (S198, S199, S202, T205) and (S212, S214, S217) respectively, are observed to be > 90% modified in AD in the FLEXITau data.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“Cluster d contains 10 symptomatic patients with late stage AD pathology Braak IV-VI and 16 asymptomatic controls at Braak 0–II.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“ANOVA analysis showed higher Tau and Ab levels in clusters with a higher Braak stage and increased level of Tau PTMs (Figure 2B).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“We identified 95 distinct PTMs on 88 amino acid residues across all samples and fractions, with a cumulative sequence coverage of 96% from detected modified and unmodified 2N4R Tau peptides (Figure 1E).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“Some of the 88 sites of modification mapped are modified by a single type of PTM; however, others can carry multiple types of modifications, such as K311, which can be ubiquitinated or acetylated.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“In this study, we show that 17 ubiquitin sites are specific to pathological Tau (14 in BA46; Figure S2C).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“A large percentage of AD patients cluster into two major groups (Figure 2A, b and c), whereas the controls fall into two clusters (Figure 2A, a and d).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“Instead, the 1N isoform is depleted significantly, and the 0N isoform is enriched in the insoluble fraction.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Concentrations and Isoform Distributions in AD and Control Subjects
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“FLEXITau quantified a total of 24 Tau peptides; of these, some were isoform specific, achieving a total sequence coverage of 61% for the 2N4R Tau isoform (Figure 1D).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Concentrations and Isoform Distributions in AD and Control Subjects
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“A high frequency of acetylation occurs in the R4 region, including the sites K353, K369, K370, and K375, whereas ubiquitination occurs in R1–R3.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“in the insoluble fraction containing pathologic Tau, 0N and 1N Tau were enriched significantly compared with the 2N isoform, and the 4R isoform is enriched significantly compared with the 3R isoform.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Concentrations and Isoform Distributions in AD and Control Subjects
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“The Braak stage of cluster b is V, whereas the Braak stage of cluster c is VI”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“Nineteen distinct acetylation sites were mapped in BA39 and 18 in BA46.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
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“Clusters b and c display many of the same PTMs; however, in cluster c, we observe a higher frequency of several PTMs, including T175, S237, and K281 (and S113, S191, and T205, which are difficult to observe at lower stoichiometry, particularly because S113 is a phosphosite found on a 0N Tau peptide).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“These PTMs include phosphorylation occurring at adjacent sites (S262 and S263), acetylation (K311, K353, and K369), and ubiquitination (K259, K267, K311, and K317).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
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“These data indicate that there is an increase in the number of PTMs and the occupancy of these PTM sites observed at different stages of disease”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Stoichiometric PTM Maps of Human Pathologic Tau Identify Critical Steps in Disease Progression
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“Our analysis of pathological Tau from 91 subjects (49 AD and 42 control subjects) cumulatively identifies 95 PTMs at 88 aa residues. We mapped 55 phosphosites, 17 ubiquitination sites, 19 acetylation sites, and four methylation sites along the length of the Tau protein.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
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“The seeding-incompetent AD and control Tau sarkosyl-soluble fractions show no differences; both are enriched in the N-terminal regions (Figure 4C).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
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“Although the unmodified C-terminal peptide is found with low abundance in AD compared to all controls, there is a control cluster where the C terminus is completely unmodified (Figure 3A) and the other control cluster shows some processing.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Peptide Stoichiometry Data Identify Key Pathological Features in Disease
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“Unsupervised analyses based on the presence or absence of PTMs clustered the subjects into 4 major groups and revealed that there were specific combinations of PTMs in each of these groups.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
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“the PRR appears to accumulate phosphosites and the MBD appears to accumulate acetylation and ubiquitination with increasing size of Tau aggregates.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
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“HMW Tau, which is thought to be oligomeric Tau, displays 20 phosphosites (6 in the N terminus, 10 in the PRR, and 4 in the C-terminal region) as well as 3 acetylation and 4 ubiquitin sites in the MBD.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
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“LMW Tau shows a similar modification pattern to Tau as the sarkosyl-soluble fraction, with 6 phosphorylations (T181, S199, S202, and T231) in the PRR being consistently observed sites in LMW and sarkosyl-soluble fractions.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
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“The N-specific region is largely underrepresented (45–67, 68–87, and 88–126), as is the C terminus in AD.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Peptide Stoichiometry Data Identify Key Pathological Features in Disease
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In the paper
“Comparative analysis of the two seeding-competent fractions, HMW Tau and the larger, fibrillized, insoluble Tau, shows a similar pattern; however, the MBD is even more enriched in the insoluble Tau fraction, and the peptide 260–267 is underrepresented, indicating a higher phosphorylation stoichiometry of this peptide (S262 and T263).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
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“These sites include three KXGS motifs”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
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“Although acetylation and ubiquitination are observed in the MBD of HMW Tau”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
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“The patient frequency of these PTMs is high; however, the stoichiometry of these sites is ~50%; thus, every second Tau molecule in a fibril is modified.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, the increase in these modifications correlates positively with increasing polymer length and increased abundance of pathological Tau associated with disease progression.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“we previously developed a targeted, high-throughput quantitative mass spectrometry (MS) method called FLEXITau (full-length expressed stable isotope-labeled Tau) (Mair et al., 2016), which provides absolute quantification and unbiased stoichiometric information of Tau PTMs from the N to the C terminus.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Mair et al., 2016
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Tau forms intracellular neurofibrillary tangles (NFTs) (Grundke-Iqbal et al., 1986; Kosik et al., 1986; Wood et al., 1986)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Grundke-Iqbal et al., 1986
- Not checked yetcites Kosik et al., 1986
- Not checked yetcites Wood et al., 1986
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Tens of possible PTM sites have been described for Tau in studies involving in vitro (Hanger et al., 2007; Martin et al., 2013a, 2013b) and in vivo AD mouse models (Morris et al., 2015; Tramutola et al., 2018) and in postmortem human studies (Hanger et al., 2007; Min et al., 2015).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Hanger et al., 2007
- Not checked yetcites Martin et al., 2013a
- Not checked yetcites Morris et al., 2015 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Besides phosphorylation, the neurofibrillary aggregates are also subject to a wide range of other PTMs (Hanger et al., 2007)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Hanger et al., 2007
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Aβ forms extracellular plaques (Glenner and Wong, 1984; Masters et al., 1985)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Glenner and Wong, 1984
- Not checked yetcites Masters et al., 1985
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“pathological neurofibrillary Tau aggregates show a pattern of accumulation that starts in the entorhinal cortex and spreads through connected pathways to cortical areas (Jucker and Walker, 2013)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Jucker and Walker, 2013 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The majority of subjects in d are listed as control subjects, and these PTMs are likely to be the earliest signs of pathology.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
hedgedconditionaln = 16- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“they cannot accurately measure quantitative changes or determine PTM stoichiometry.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The discovery of dominantly inherited Tau mutations leading to frontotemporal dementia (FTD) (Poorkaj et al., 1998; Spillantini et al., 1998)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that early disease is observed in a few controls.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Qualitative and Quantitative Maps of Tau PTMs and Their Frequency in AD Patient
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“brain lysates seed Tau aggregation when high-molecular-weight oligomeric hyperphosphorylated (AT8 and AT100) Tau species are present (Takeda et al., 2015; Jackson et al., 2016)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Takeda et al., 2015 source
- Not checked yetcites Jackson et al., 2016
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Combinations of such PTMs are responsible for regulating and fine-tuning protein conformation and activity (Aebersold et al., 2018; Soria et al., 2014)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Aebersold et al., 2018 source
- Not checked yetcites Soria et al., 2014
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“This encompasses a cycle that involves production of a Tau seed followed by uptake of seed-competent Tau into connected cells (Clavaguera et al., 2013)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Clavaguera et al., 2013
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests that the modification at the C terminus is an early event during aging and AD pathology and can most likely be attributed to caspase-3 and −6 cleavage at D418 and D421.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Peptide Stoichiometry Data Identify Key Pathological Features in Disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“which has been shown to form the core region of the Tau filaments (Fitzpatrick et al., 2017).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
What the sources say
- Not checked yetcites Fitzpatrick et al., 2017
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“which are known to regulate neurite extension and binding of Tau to microtubules (Biernat et al., 1993; Biernat and Mandelkow, 1999).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
What the sources say
- Not checked yetcites Biernat et al., 1993
- Not checked yetcites Biernat and Mandelkow, 1999
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, these data suggest that early intervention may need different therapeutic agents than late-stage AD because there are distinct differences in PTM profiles associated with each stage of disease.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This increase in phosphorylation of Tau may be involved in neutralizing the charge in the MBD domain to promote aggregation”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Tau Peptide Stoichiometry Data Identify Key Pathological Features in Disease
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The sets of PTMs were largely reflective of disease progression and therefore could be associated with disease stages.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The above results from sarkosyl-insoluble (fibrillized) Tau from AD and control subjects indicate that there is processivity and an order in which PTMs occur in the fibrillization process.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“an observation partially consistent with recent Tau PTM mapping results in mice (Morris et al., 2015; Table S5).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
What the sources say
- Not checked yetcites Morris et al., 2015 source
hedgedcorrelationaln = 91- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To ensure no bias in acquisition, samples were run in randomized order (three technical replicates per sample).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, all MS/MS spectra of identified post-translationally modified peptides were subjected to manual verification.”
- Also stated in: § Preparation and MS analysis of MC1-isolated Tau · plain
“Spectra for identified modified peptides were manually validated.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of high and low molecular weight Tau and mass spectrometric analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § Preparation and MS analysis of MC1-isolated Tau · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that the 0N and 4R version, when phosphorylated, is no longer disordered and can adopt a structure capable of fibril formation.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, all MS/MS spectra of identified post-translationally modified peptides were subjected to manual verification.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All peptide transitions were evaluated for variability, similarity between y-ion ratios, elution times, and interfering signals by manual analysis.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Peptides were considered ‘quantifiable’ if the peptide transitions had a signal-to-noise of > 3 and at least three light and three heavy high-quality SRM transitions were observed.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“which would be charged positively at physiological pH and experience repulsive electrostatic forces, preventing formation of a b sheet fibril structure.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Tau contains 19 lysine residues in its microtubule-binding domain.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Increased phosphorylation in the PRR results in accumulation of negative charges, which, we postulate, could neutralize the positive charge in the MBD”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“False discovery rate (FDR) was set to 1% on peptide and protein levels with a minimum length of seven amino acids and was determined by searching a reverse database.”
- Also stated in: § Preparation and MS analysis of MC1-isolated Tau · plain
“False discovery rate (FDR) was set to 1% on peptide and protein level and was determined by searching a reverse database.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Also stated in: § Preparation and MS analysis of MC1-isolated Tau · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Randomized samples (SEC fractions 2,3,4 and 14,16,18 for 4 AD and 4 control human brain samples) were analyzed in duplicates using a Q Exactive mass spectrometer”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of high and low molecular weight Tau and mass spectrometric analysis
plainn = 4- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Randomized samples (SEC fractions 2,3,4 and 14,16,18 for 4 AD and 4 control human brain samples) were analyzed in duplicates using a Q Exactive mass spectrometer”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of high and low molecular weight Tau and mass spectrometric analysis
plainn = 4- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A cutoff of 85% confidence was employed for all modified peptides.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of high and low molecular weight Tau and mass spectrometric analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Peak boundaries were manually inspected and reassigned as needed to ensure correct peak detection and accurate integration.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A cutoff of 85% confidence was employed for all modified peptides.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of brain tissue samples and mass spectrometry analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data support a processive model (Figure 5C) where 0N and 4R are predisposed to aggregation, cleavage of the C terminus enables fibrillization, followed by phosphorylation in the PRR domain and acetylation and ubiquitination in the MBD, which remove electrostatic repulsion of positively charged lysine residues in this region, promoting Tau fibrilization.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Western Blot analysis using Tau13, Tau46, HT7 and DAKO antibodies confirmed that the fraction 3 and 4 are enriched for Tau (data not shown).”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > METHOD DETAILS > Preparation of high and low molecular weight Tau and mass spectrometric analysis
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The authors state this as an assumption.
A qualitative and quantitative approach using a large cohort of human AD subjects had not been performed before this study.
“To our knowledge, a qualitative and quantitative approach using a large cohort of human AD subjects has not been performed.”
The authors state this as an assumption.
The minimum set of PTMs important for oligomer formation and Tau aggregation is not known.
“Furthermore, the minimum set of PTMs important for oligomer formation and Tau aggregation is not known.”
The authors state this as an assumption.
Which PTMs occur on Tau seeds that can potentiate further aggregation is not known.
“Finally, it is not known which PTMs occur on Tau seeds that can potentiate further aggregation.”
The paper relies on this without support.
Tau contains 19 lysine residues in its microtubule-binding domain.
“Tau has 19 lysine residues in the MBD”
The paper relies on this without support.
The disordered regions of Tau include the N terminus and the proline-rich region.
“The disordered regions of Tau span the N terminus and PRR.”
The paper relies on this without support.
HMW Tau is oligomeric Tau.
“HMW Tau, which is thought to be oligomeric Tau”
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?
In the citing paper
“In examining the clinical records, we found that those cases with the most marked propagation potential also had the fastest clinical course and had characteristic patterns of post-translational modifications (10, 11).”
From All the Tau We Cannot See (2023) · cites this paper as [11]
In the citing paper
“For example, the microtubule-associated protein tau is often measured using antibodies that represent phosphorylation at threonine 181 and one that measures so called “total-tau”. However, at least 95 post-translational modifications have been discovered on tau with potentially many 100s of possible proteoforms resulting from the combinations.(16)”
From Putting humpty dumpty back together again: what does protein quantification mean in bottom-up proteomics? (2022) · cites this paper as [16]
In the citing paper
“Additional studies indicate that specific tau phosphosites may be better indicators of disease progression, emphasizing the importance of distinguishing between different pTau isoforms and proteoforms.(15,16)”
From Putting humpty dumpty back together again: what does protein quantification mean in bottom-up proteomics? (2022) · cites this paper as [16]
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.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
“we observe acetylation and ubiquitination as being unique to seeding-positive Tau compared with LMW and sarkosyl-soluble seeding-negative fractions.”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > DISCUSSION
“Ubiquitination is unique to seeding-competent Tau, whereas acetylation is also observed in seeding-incompetent Tau.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Individual Tau PTM Profiles Show Heterogeneity and Reflect Disease Progression
“These PTMs include phosphorylation occurring at adjacent sites (S262 and S263)”
§ Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease > RESULTS > Identifying PTMs Associated with Seeding Activity in Size-Fractionated Tau
“indicating a higher phosphorylation stoichiometry of this peptide (S262 and T263).”
Citations
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MethodMirra, S. S., Heyman, A., McKeel, D., Sumi, S. M., Crain, B. J., Brownlee, L. M., Vogel, F. S., Hughes, J. P., Belle, G. V., Berg, L., et al. (1991) · Neurology · doi:10.1212/wnl.41.4.479 · Cited by 4,961 · cited 1×
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MethodSkyline: an open source document editor for creating and analyzing targeted proteomics experiments
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“Aβ forms extracellular plaques (Glenner and Wong, 1984; Masters et al., 1985), whereas Tau forms intracellular neurofibrillary tangles (NFTs) (Grundke-Iqbal et al.”
Background
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Microtubule Binding of a Tau Peptide Monitored through Fluorine NMR Probes
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Metadata
- Authors
- Wesseling, H., Mair, W., Kumar, M., Schlaffner, C. N., Tang, S., Beerepoot, P., Fatou, B., Guise, A. J., Cheng, L., Takeda, S., Muntel, J., Rotunno, M. S., Dujardin, S., Davies, P., Kosik, K. S., Miller, B. L., Berretta, S., Hedreen, J. C., Grinberg, L. T., Seeley, W. W., Hyman, B. T., Steen, H., & Steen, J. A.
- Affiliations
- Boston Children's Hospital (US)
- Harvard University (US)
- Feinstein Institute for Medical Research (US)
- University of California, Santa Barbara (US)
- University of California, San Francisco (US)
- Corresponding author
- Steen, Judith A.
- ORCID
- Kumar, Mukesh
- Schlaffner, Christoph N.
- Tang, Shaojun
- Beerepoot, Pieter
- Fatou, Benoit
- Guise, Amanda J.
- Cheng, Long
- Takeda, Shuko
- Muntel, Jan
- Dujardin, Simon
- Davies, Peter
- Kosik, Kenneth S.
- Miller, Bruce L.
- Berretta, Sabina
- Hedreen, John C.
- Grinberg, Lea T.
- Seeley, William W.
- Hyman, Bradley T.
- Steen, Hanno
- Steen, Judith A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 183
- Issue
- 6
- Pages
- 1699-1713.e13
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8168922
- OpenAlex
- W3102160053
- Semantic Scholar
- eb7657dfe7b98f7376299bf9d45805d3dc70eb6d
- Cited by
- 688
- References
- 78
- Citations by year
- 2026: 104 · 2025: 132 · 2024: 140 · 2023: 112 · 2022: 109 · 2021: 88 · 2020: 2
- FWCI
- 47.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- Tau Consortium
- Topics
- 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
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- Alzheimer's disease, tau protein, post-translational modification, tau isoforms, tau aggregation, seeding activity, patient heterogeneity, disease staging, proline-rich region, microtubule-binding domain, postmortem brain, quantitative proteomics
- MeSH terms
- Alzheimer Disease, Humans, Protein Processing, Post-Translational, Cohort Studies, Case-Control Studies, tau Proteins, Disease Progression, Protein Isoforms, Principal Component Analysis
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.
A language model drew the claims from the paper on 2026-10-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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