Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease

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

Evidence from AD neuronal culture models indicates that soluble Aβ oligomers induce tau hyperphosphorylation in multiple sites.

“Interestingly, evidence from AD neuronal culture models indicate that soluble Aβ oligomers (AβOs) induce tau hyperphosphorylation in multiple sites.16,17”

• cites [16] De Felice, 2008, Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers, Neurobiol Aging sourceSupported
• cites [17] Sackmann, 2020, Oligomeric amyloid-beta induces early and widespread changes to the proteome in human iPSC-derived neurons, Sci Rep sourceDisputed

  The Discussion reports increased tau phosphorylation at Ser208 after oligomeric Aβ exposure, but says other canonical tau phosphorylation sites were not remarkably altered after 24 hours. Its finding is therefore contrary to the attributed claim of hyperphosphorylation at multiple sites. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

CSF concentrations of t-tau and p-tau are proposed to reflect neurodegeneration and tau pathology in the form of NFTs, respectively.

“Specifically, CSF concentrations of t-tau and p-tau are proposed to reflect neurodegeneration and tau pathology in the form of NFTs, respectively.7”

• cites [7] Jack, 2018, NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease, Alzheimers Dement sourceSupported

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

CSF p-tau217 might better discriminate AD from other neurodegenerative diseases than CSF p-tau181.

“Recent reports have suggested that CSF p-tau217 might better discriminate AD from other neurodegenerative diseases24,27, 28, 29, 30 than CSF p-tau181.”

• cites [24] Janelidze, 2020, Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease, Nat Commun sourceSupported
• cites [27] Barthelemy, 2020, Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer's disease and PET amyloid-positive patient identification, Alzheimers Res Ther sourceSupported
• cites [28] Karikari, 2020, Head-to-head comparison of clinical performance of CSF phospho-tau T181 and T217 biomarkers for Alzheimer's disease diagnosis, Alzheimers Dement sourceSupported
• cites [29] Mielke, 2021, Comparison of CSF phosphorylated tau 181 and 217 for cognitive decline, Alzheimers Dement sourceSupported
• cites [30] Leuzy, 2021, Comparing the clinical utility and diagnostic performance of CSF P-Tau181, P-Tau217, and P-Tau231 Assays, Neurology sourceSupported

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

CSF p-tau217 correlates better with Aβ and tau PET imaging than CSF p-tau181.

“In addition, CSF p-tau217 correlates better with Aβ and tau PET imaging than CSF p-tau181.24,30”

• cites [24] Janelidze, 2020, Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease, Nat Commun sourceSupported
• cites [30] Leuzy, 2021, Comparing the clinical utility and diagnostic performance of CSF P-Tau181, P-Tau217, and P-Tau231 Assays, Neurology sourceSupported

May combine two claims.

CSF p-tau231 increases early in the AD continuum and may detect preclinical AD among cognitively unimpaired individuals.

“We have recently reported that CSF p-tau231 increases early in the AD continuum and, therefore, may detect preclinical AD among cognitively unimpaired (CU) individuals.31”

• cites [31] Suarez-Calvet, 2020, Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Abeta pathology are detected, EMBO Mol Med sourceSupported

May combine two claims.

These biomarkers (t-tau and p-tau) remain at normal concentrations in other neurodegenerative disorders with substantial neurodegeneration, and also those with tau pathology.

“However, these biomarkers remain at normal concentrations in other neurodegenerative disorders with substantial neurodegeneration,8, 9, 10 and also those with tau pathology.11, 12, 13”

• cites [8] Riemenschneider, 2003, Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt-Jakob disease from other dementias, Mol Psychiatry sourceNot checked — no full text of the source
• cites [9] Skillback, 2014, Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease: results from the Swedish mortality registry, JAMA Neurol sourceNot checked — no full text of the source
• cites [10] Schoonenboom, 2012, Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort, Neurology sourceNot checked — no full text of the source
• cites [11] Hampel, 2004, Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study, Arch Gen Psychiatry sourceNot checked — no full text of the source
• cites [12] Leuzy, 2020, Diagnostic performance of RO948 F 18 tau positron emission tomography in the differentiation of Alzheimer disease from other neurodegenerative disorders, JAMA Neurol sourceCould not verify

  The Introduction (page unavailable) says that tau pathology occurs in non-Alzheimer neurodegenerative disorders, and the Conclusions (page unavailable) discuss the diagnostic performance of CSF p-tau181. Neither passage establishes that CSF t-tau and p-tau remain at normal concentrations in those disorders, including those with tau pathology. Searches for their concentrations in non-Alzheimer disorders did not find that result in our copy. (LLM, conf=0.73)

  Experimental — accuracy not yet measured
• cites [13] La Joie, 2018, Associations between [(18)F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample, Neurology sourcePartly supported

  The Abstract (page unavailable) reports that CSF p-tau distinguishes Alzheimer disease from non-AD neurodegenerative conditions, lending support to a difference in biomarker levels. It does not establish that both p-tau and t-tau remain at normal concentrations in disorders with tau pathology; that stronger, disorder-specific claim is unsupported by the passages in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Early removal of Aβ seeds, before Aβ deposition becomes detectable, led to a significant reduction of Aβ accumulation and downstream pathologies in transgenic mice.

“a recent study in transgenic mice suggests that early removal of Aβ seeds, before Aβ deposition becomes detectable, led to a significant reduction of Aβ accumulation and downstream pathologies.32”

• cites [32] Uhlmann, 2020, Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life, Nat Neurosci sourceSupported

May combine two claims.

CSF p-tau biomarkers likely indicate an active process of tau secretion, and one that is correlated with cerebral Aβ deposition in early disease.

“Thus, it is suggested that CSF p-tau biomarkers likely indicate an active process of tau secretion, and one that is correlated with cerebral Aβ deposition in early disease.20, 21, 22”

• cites [20] Bateman, 2012, Clinical and biomarker changes in dominantly inherited Alzheimer's disease, N Engl J Med sourcePartly supported

  The Methods (Biochemical Analysis; page unavailable) say the study measured CSF phosphorylated tau. The Results (Combined Model; page unavailable) place increased CSF tau and cerebral Aβ deposition about 15 years before expected symptom onset in mutation carriers. These findings support their early co-occurrence, but the paper does not establish active tau secretion or a correlation specifically between CSF p-tau and cerebral Aβ deposition. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [21] Toledo, 2013, Longitudinal change in CSF Tau and Abeta biomarkers for up to 48 months in ADNI, Acta Neuropathol sourcePartly supported

  The Results and Discussion (page unavailable) report that low baseline CSF Aβ1–42 was associated with subsequent increases in CSF p-tau181, supporting a relationship between the biomarkers in the studied cohort. They do not establish that p-tau indicates active tau secretion or directly show a correlation with cerebral Aβ deposition; the association measured here was with CSF Aβ1–42. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [22] Brunello, 2020, Mechanisms of secretion and spreading of pathological tau protein, Cell Mol Life Sci sourcePartly supported

  The Cell-to-cell transfer of tau section says CSF in AD contains elevated phosphorylated tau and that active cellular processes contribute to tau secretion. The paper also discusses amyloid pathology as a possible trigger for tau release, but it does not state that CSF p-tau biomarkers correlate with cerebral Aβ deposition in early disease. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

CSF p-tau epitopes increase in the preclinical phase of the disease, prior to symptom onset and before substantial tau PET ligand retention.

“Our data, like prior studies,18,28,31 shows an increase of CSF p-tau epitopes in the preclinical phase of the disease, prior to symptom onset and before substantial tau PET ligand retention.”

• cites [18] Barthelemy, 2020, A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease, Nat Med sourceSupported
• cites [28] Karikari, 2020, Head-to-head comparison of clinical performance of CSF phospho-tau T181 and T217 biomarkers for Alzheimer's disease diagnosis, Alzheimers Dement sourcePartly supported

  The Introduction reports that CSF p-tau217 begins to increase in preclinical familial Alzheimer’s disease, supporting an increase before symptoms. The Discussion also describes early increases in N-terminal p-tau biomarkers. Neither passage establishes that these increases precede substantial tau-PET ligand retention; the Introduction reports a correlation with tau-PET, not that timing. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [31] Suarez-Calvet, 2020, Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Abeta pathology are detected, EMBO Mol Med sourceSupported

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

P-tau231 levels in blood have recently been demonstrated to increase earlier than p-tau181, but a direct comparison with p-tau217 in early preclinical disease is not currently available.

“P-tau231 levels in blood have also recently been demonstrated to increase earlier than p-tau18160 (Tissot et al., 2022), however, a direct comparison with p-tau217 in early preclinical disease is not currently available.”

• cites [60] Ashton, 2021, Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology, Acta Neuropathol sourceSupported
• cites Tissot et al., 2022Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

In sporadic AD, CSF p-tau is closely related to Aβ-mediated tau release from neurons and is not simply a state marker of NFT.

“Thus, in relation to sporadic AD, this study adds further support to the hypothesis that CSF p-tau is closely related to Aβ-mediated tau release from neurons19 and challenges the notion of being simply a state marker of NFT.”

• cites [19] Sato, 2018, Tau kinetics in neurons and the human central nervous system, Neuron sourcePartly supported

  The Results section reports that CSF tau production, including synthesis and release, correlates with amyloid burden; the Discussion proposes that this increase can precede tau aggregation. But the amyloid–release analysis concerns tau overall, not specifically CSF p-tau, and it does not establish that Aβ causes neuronal p-tau release. The paper therefore supports the broader hypothesis, but not the claim at that level of specificity. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Previous neuropathological findings highlighted that a key component of pre-tangle pathology was phosphorylation at threonine 231 and that CSF p-tau231 is an important discriminant of Braak 0-I from more advanced Braak stages.

“Previous neuropathological findings, which motivated the CSF assay development of p-tau231, highlighted that a key component of pre-tangle pathology was phosphorylation at threonine 23155 and that CSF p-tau231 is an important discriminant of Braak 0-I from more advanced Braak stages.56”

• cites [55] Augustinack, 2002, Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease, Acta Neuropathol sourceNot checked — no full text of the source
• cites [56] Ercan-Herbst, 2019, A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer's disease brain, Acta Neuropathol Commun sourcePartly supported

  The Discussion links pT231 to pre-tangle structures, and the Results report higher pT231 in brain tissue at Braak III–IV than at Braak 0–I. The paper also says CSF pT231 is increased in AD patients, but it does not show that CSF p-tau231 discriminates between Braak stages; its Braak comparison used brain tissue. In the citing sentence, the citation to this paper is attached to the CSF discrimination claim. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

[18F]MK6240 detects paired helical filament (PHF) tau and has shown a high binding affinity for brain homogenate rich in NFTs.

“[18F]MK6240 detects paired helical filament (PHF) tau and has shown a high binding affinity for brain homogenate rich in NFTs.61”

• cites [61] Malarte, 2020, Characterization of MK6240, a tau PET tracer, in autopsy brain tissue from Alzheimer's disease cases, Eur J Nucl Med Mol Imaging sourcePartly supported

  The Introduction reports high affinity of MK6240 for NFT-rich brain homogenate, and the paper’s binding assays support high affinity for tau deposits in Alzheimer’s disease tissue. The copy describes binding to tau fibrils but does not specifically identify the detected tau as paired helical filament (PHF) tau. Its own tissue-binding experiments used 3H-MK6240 rather than 18F-MK6240. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Tau phosphorylation at threonine 231 is one of the earliest events in the cascade of phosphorylation and modulates tubulin assembly.

“Tau phosphorylation at threonine 231 is one of the earliest events in the cascade of phosphorylation,57 that modulates tubulin assembly.58”

• cites [57] Castellani, 2019, Tau biology, tauopathy, traumatic brain injury, and diagnostic challenges, J Alzheimers Dis sourcePartly supported

  In “Tau protein phosphorylation and hyperphosphorylation” (page unavailable), the paper discusses phosphorylated tau at the Thr231 proline motif, but does not say Thr231 phosphorylation is among the earliest events in a phosphorylation cascade. “Normal tau function” (page unavailable) says tau promotes tubulin polymerization, but does not link that effect specifically to Thr231 phosphorylation; the citing sentence attaches a separate citation to its assembly clause. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [58] Amniai, 2009, Alzheimer disease specific phosphoepitopes of Tau interfere with assembly of tubulin but not binding to microtubules, FASEB J sourceNot checked — no full text of the source

May combine two claims.

Increases in CSF p-tau231 are related to early Aβ seeds and could act as a key biomarker for the pre-amyloid phase of AD, which occurs before the Aβ deposition threshold.

“Thus, one could propose that increases in CSF p-tau231 are related to early Aβ seeds and could act as a key biomarker for the recently described “pre-amyloid phase” of AD, which occurs before Aβ deposition threshold.32”

• cites [32] Uhlmann, 2020, Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life, Nat Neurosci sourceSupported

May combine two claims.

CSF p-tau231 becomes abnormal first and seems the principal p-tau candidate to identify early Aβ seeds in the pre-amyloid phase, which is currently seen as the optimal period for therapeutic intervention.

“Specifically, CSF p-tau231 becomes abnormal first and seems the principal p-tau candidate to identify early Aβ seeds in the recently proposed “pre-amyloid phase”,32 which is currently seen as the optimal period for therapeutic intervention.”

• cites [32] Uhlmann, 2020, Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life, Nat Neurosci sourcePartly supported

  The Abstract and Discussion describe a pre-amyloid phase with targetable Aβ seeds and propose intervention before detectable deposition, based on a mouse model. They do not establish that CSF p-tau231 becomes abnormal first or is the principal marker of those seeds; the Discussion also says the efficacy of early seed removal in humans has not been established. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: The pre-amyloid phase is the optimal period for therapeutic intervention.

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

CSF p-tau231 has been widely reported as a biomarker to detect AD at both the MCI and dementia stages, but often it has been concluded that these changes are not different from CSF p-tau181 when directly compared.

“CSF p-tau231 has been widely reported as a biomarker to detect AD at both the MCI and dementia stages of disease11,49, 50, 51, 52, 53 but often it has been concluded these changes are not different from CSF p-tau181 when directly compared.54”

• cites [11] Hampel, 2004, Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study, Arch Gen Psychiatry sourceNot checked — no full text of the source
• cites [49] Santos, 2019, Validation of a prototype tau Thr231 phosphorylation CSF ELISA as a potential biomarker for Alzheimer's disease, J Neural Transm sourceNot checked — no full text of the source
• cites [50] Spiegel, 2016, Greater specificity for cerebrospinal fluid P-tau231 over P-tau181 in the differentiation of healthy controls from Alzheimer's disease, J Alzheimers Dis sourcePartly supported

  The Introduction reports that one meta-analysis found P-tau181 and P-tau231 comparably good for AD diagnosis, supporting the claim that a direct comparison has found them similar. But it does not establish that this was often concluded, and the paper’s Discussion concludes that P-tau231 was superior at separating AD patients from normal controls. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

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.”

• cites [20] Bateman, 2012, Clinical and biomarker changes in dominantly inherited Alzheimer's disease, N Engl J Med sourcePartly supported

  The Results (Biochemical Measures and Combined Model; page not provided) report increased CSF tau about 15 years before expected symptom onset, preceding FDG-PET hypometabolism at about 10 years. But brain atrophy was detected at the same time as increased CSF tau, not later. The paper measured phosphorylated tau but does not establish the claimed sequence relative to tau PET or neurofilament light, or the conclusion about NFT leakage. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [63] Mattsson-Carlgren, 2020, Abeta deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer's disease, Sci Adv sourceSupported
• cites [64] Gordon, 2019, Tau PET in autosomal dominant Alzheimer's disease: relationship with cognition, dementia and other biomarkers, Brain sourcePartly supported

  The Discussion says CSF measures of tauopathy likely become abnormal before tau PET measures, supporting the timing comparison to which this citation is attached. It also says the timing results are qualitative and that larger studies are needed to establish the order definitively; the citing sentence states that order as fact. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

No statistical superiority was demonstrated for p-tau217 over p-tau231, but higher fold changes between AD and all other clinical groups were observed for p-tau217.

“While no statistical superiority was demonstrated for p-tau217 over p-tau231, we did observe higher fold changes between AD and all other clinical groups for p-tau217 which is consistent with more recent findings.30”

• cites [30] Leuzy, 2021, Comparing the clinical utility and diagnostic performance of CSF P-Tau181, P-Tau217, and P-Tau231 Assays, Neurology sourceSupported

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

Soluble AβOs enhance kinase activity triggering tau hyperphosphorylation at threonine 231 in primary neuronal cultures.

“Interestingly, soluble AβOs are known to enhance kinase activity triggering tau hyperphosphorylation at threonine 231 in primary neuronal cultures.16”

• cites [16] De Felice, 2008, Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers, Neurobiol Aging sourcePartly supported

  Results §§3.3 and 3.5 show that Aβ oligomers induced tau phosphorylation at Thr231 in primary hippocampal neuronal cultures and that Src-family kinase and PI3K inhibitors blocked it. The inhibitor results implicate kinase signaling, but the paper does not establish that the oligomers enhanced kinase activity; the Discussion presents pathway activation as a possibility. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

In CI individuals, no CSF p-tau was found to be significantly superior, although CSF p-tau217 had numerically the highest AUC (0.99; 95% CI, 0.99-1.00).

“Conversely, in CI individuals, no CSF p-tau was found to be significantly superior, although CSF p-tau217 had numerically the highest AUC (0.99; 95% CI, 0.99-1.00).”

May combine two claims.

No significant differences were found between the CSF biomarkers when predicting tau PET positivity and all demonstrated comparable AUC values (AUC = 0.86-0.93).

“No significant differences were found between the CSF biomarkers when predicting tau PET positivity and all demonstrated comparable AUC values (AUC = 0.86-0.93, Figure 2d).”

May combine two claims.

All biomarkers had high accuracies (AUC > 0.96) in separating AD from non-AD and no biomarker was found to be statistically superior in this comparison.

“All biomarkers had high accuracies (AUC > 0.96) in separating AD from non-AD and no biomarker was found to be statistically superior in this comparison.”

May combine two claims.

No marked difference was observed between CSF p-tau231 and CSF p-tau217, whilst CSF p-tau181 indicated weaker associations narrowed to reduced regions if compared to the other biomarkers.

“No marked difference was observed between CSF p-tau231 and CSF p-tau217, whilst CSF p-tau181 indicated weaker associations narrowed to reduced regions if compared to the other biomarkers (Figure 2e).”

May combine two claims.

Correlations were inferior for CSF p-tau181 (r = 0.70) which were significantly different to other p-tau biomarkers (Pp-tau231 vs p-tau181< 0.001; Pp-tau217 vs p-tau181= 0.01).

“Once more, correlations were inferior for CSF p-tau181 (r = 0.70, P < 0.001, Figure 3c) which were significantly different to other p-tau biomarkers (Pp-tau231 vs p-tau181< 0.001; Pp-tau217 vs p-tau181= 0.01).”

May combine two claims.

CSF p-tau217 demonstrated the largest fold increase between CI Aβ+ and CI Aβ- (4.7-fold, P < 0.002), but this was not significantly different to other CSF p-tau biomarkers.

“Similarly, CSF p-tau217 demonstrated the largest fold increase between CI Aβ+ and CI Aβ- (4.7-fold, P < 0.002; supplementary table 2). However, this was not significantly different to other CSF p-tau biomarkers.”

May combine two claims.

CSF p-tau217 was 6-fold higher in CI Aβ+ than in CU Aβ-, which was a significantly larger increase than other p-tau biomarkers (Pp-tau231=0.002; Pp-tau181=0.01).

“CSF p-tau217 was 6-fold higher in CI Aβ+ than in CU Aβ-, which was a significantly larger increase than other p-tau biomarkers (Pp-tau231=0.002; Pp-tau181=0.01; supplementary table 2).”

May combine two claims.

In CU participants, a stronger relationship between [18F]MK6240 and CSF p-tau231 and CSF p-tau217 (TCU>3.16; PCU<0.05) was found, with significant associations confined to temporal regions corresponding to Braak stage regions I-IV.

“A stronger relationship between [18F]MK6240 and CSF p-tau231 and CSF p-tau217 (TCU>3.16; PCU<0.05) were found in CU participants, with significant associations confined to temporal regions corresponding to Braak stage regions I-IV (Figure 2g).”

May combine two claims.

CSF p-tau231 (AUC = 0.95) and CSF p-tau217 (AUC = 0.95) were significantly better predictors of Aβ PET status than CSF p-tau181 (AUC = 0.88; both P < 0.01).

“CSF P-tau231 (AUC = 0.95; 95% CI, 0.92-0.98) and CSF p-tau217 (AUC = 0.95; 95% CI, 0.92-0.99) were significantly better predictors of Aβ PET status than CSF p-tau181 (AUC = 0.88; 95% CI, 0.81-0.94; both P < 0.01, Figure 3d).”

May combine two claims.

CSF p-tau181 showed a noticeable decline in performance when distinguishing MCI from non-AD (AUC = 0.83; 95% CI, 0.67-0.99) and MCI from CU (AUC = 0.81; 95% CI, 0.66-0.96), which was significantly different to p-tau231 and p-tau217 (P < 0.05).

“A noticeable decline in performance was observed for CSF p-tau181 when distinguishing MCI from non-AD (AUC = 0.83; 95% CI, 0.67-0.99) and MCI from CU (AUC = 0.81; 95% CI, 0.66-0.96) which was significantly different to p-tau231 and p-tau217 (P < 0.05 [DeLong's]).”

May combine two claims. The quote only partly states this claim.

CSF p-tau217 demonstrated the largest fold-changes in AD patients compared to non-AD dementias and cognitively unimpaired individuals, and exhibits larger fold-changes when symptomatic disease is apparent.

“CSF p-tau217 demonstrated the largest fold-changes in AD patients in comparison to non-AD dementias and cognitively unimpaired individuals.”

• Also stated in: § Funding · plain

  “p-tau217 exhibits larger fold-changes when symptomatic disease is apparent”

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

There was no association between sex and p-tau biomarkers when adjusting for age and diagnosis.

“There was no association between sex and p-tau biomarkers when adjusting for age and diagnosis.”

May combine two claims.

In CU individuals, CSF p-tau231 (AUC = 0.91) was significantly superior to CSF p-tau181 (AUC = 0.82; P = 0.02) but not CSF p-tau217 (AUC = 0.90; P=0.75) for detecting Aβ positivity.

“In CU individuals, CSF p-tau231 (AUC = 0.91; 95% CI, 0.84-0.98) was significantly superior to CSF p-tau181 (AUC = 0.82; 95% CI, 0.71-0.93; P = 0.02) but not CSF p-tau217 (AUC = 0.90; 95% CI, 0.83-0.98; P=0.75).”

May combine two claims.

CSF biomarkers were associated with higher [18F]MK6240 uptake in the inferior, medial and lateral temporal regions (Tall>3.14; Pall<0.05), with associated areas overlapping between CSF biomarkers.

“At the voxel level, CSF biomarkers were associated with higher [18F]MK6240 uptake in the inferior, medial and lateral temporal regions (Tall>3.14; Pall<0.05, Figure 2E), with associated areas overlapping between CSF biomarkers.”

May combine two claims.

CSF p-tau181 significantly outperformed CSF p-tau231 (P < 0.01) but not CSF p-tau217 (P=0.13) in distinguishing CU from AD.

“This significantly outperformed CSF p-tau231 (P < 0.01[DeLong's]) but not CSF p-tau217 (P=0.13[DeLong's]).”

May combine two claims.

CSF p-tau231 and CSF p-tau217 were significantly increased in CU Aβ+ as compared to CI Aβ-, but this was not observed for CSF p-tau181.

“CSF p-tau231 (Figure 1a) and CSF p-tau217 (Figure 1b) were significantly increased in CU Aβ+ as compared to CI Aβ- but this was not observed for CSF p-tau181 (Figure 1c).”

May combine two claims.

CSF p-tau231 displays the largest effect size in relation to Aβ deposition, both globally and regionally, and is the first to achieve abnormal values among the biomarkers tested.

“Furthermore, we demonstrated that CSF p-tau231 displays the largest effect size in relation to Aβ deposition, both globally and regionally, and, amongst the biomarkers tested, is the first to achieve abnormal values.”

May combine two claims.

CSF biomarkers became abnormal at different pathological stages, with CSF p-tau231 positive at approximately Centiloid 37, followed by CSF p-tau181 at Centiloid 47 and CSF p-tau217 at Centiloid 50.

“Contrarily, CSF biomarkers showed to become abnormal at different pathological stages, with CSF p-tau231 status being positive at approximately Centiloid 37, followed by CSF p-tau181 at Centiloid 47 and CSF p-tau217 at Centiloid 50.”

May combine two claims.

CSF p-tau231 had the largest beta values in relation to Aβ deposition and seemingly became abnormal before CSF p-tau217 and CSF p-tau181 when pathophysiological progression was delineated by Aβ PET Centiloids.

“This was further substantiated by CSF p-tau231 having the largest beta values in relation to Aβ deposition and seemingly becoming abnormal before CSF p-tau217 and CSF p-tau181 when the pathophysiological progression was delineated by Aβ PET Centiloids.”

May combine two claims.

Using the ratio of Aβ42 to p-tau did not largely change the results but produced higher AUCs.

“Using the ratio of Aβ42 to p-tau did not largely change our results but produced higher AUC's, which should be further investigated in larger cohort sizes or utilized if the optimal p-tau is not available, as highlighted in this study.”

May combine two claims.

This study documents pronounced preclinical increases of CSF p-tau biomarkers and specifically highlights CSF p-tau231, which begins to associate with Aβ deposition before the threshold of Aβ PET positivity has occurred and strongly associates with known early Aβ accumulating regions in the DMN.

“In conclusion, this study documents the pronounced preclinical increases of CSF p-tau biomarkers but specifically highlights CSF p-tau231 which begins to associate with Aβ deposition before the threshold of Aβ PET positivity has occurred and strongly associates with known early Aβ accumulating regions in the DMN.”

May combine two claims.

CSF p-tau231 demonstrated numerically identical AUCs to CSF p-tau217 in the prediction of Aβ PET at CU stage, but only CSF p-tau231 and not CSF p-tau217 was significantly superior to CSF p-tau181.

“Although CSF p-tau231 demonstrated numerically identical AUC's to CSF p-tau217 in the prediction of Aβ PET at CU stage of the AD continuum, only CSF p-tau231 and not CSF p-tau217 was significantly superior to CSF p-tau181.”

May combine two claims.

A numerical advantage was observed in CU participants for p-tau231/Aβ42 (AUC = 0.96) and p-tau217/Aβ42 (AUC=95%).

“However, a numerical advantage was observed in CU participants (p-tau231/Aβ42, AUC = 0.96; 95% CI, 92-99%; p-tau217/Aβ42, AUC=95%; 95% CI, 91-99%).”

May combine two claims.

CSF p-tau231 and CSF p-tau217 have a similar relationship with [18F]MK6240 and [18F]AZD4694, and both are better predictors of PET status than CSF p-tau181.

“We demonstrate that CSF p-tau231 and CSF p-tau217 biomarkers have a similar relationship with [18F]MK6240 and [18F]AZD4694, being both better predictors of PET status in comparison with CSF p-tau181.”

May combine two claims.

CSF p-tau231 and CSF p-tau217 associated with [18F]MK6240 to the same degree in the whole group and at both CI and CU stages, whereas CSF p-tau181 had weaker associations.

“In this study, we found that CSF p-tau231 and CSF p-tau217 associated with [18F]MK6240 to the same degree in the whole group and at both CI and CU stages, whereas CSF p-tau181 had weaker associations.”

May combine two claims.

In CU participants without prominent Aβ pathology (Aβ-), CSF p-tau231 showed focal associations with emerging Aβ pathology in the medial orbitofrontal, precuneus and posterior/isthmus cingulate cortices, stronger than p-tau217 and absent for p-tau181.

“We further performed a voxel-wise analysis in CU participants without prominent Aβ pathology (Aβ-) and demonstrated focal associations of CSF p-tau231 with emerging Aβ pathology in the medial orbitofrontal, precuneus and posterior/isthmus cingulate cortices which were stronger than what was observed for p-tau217 and absent for p-tau181.”

Classified as probably not a substantial claim.

Voxel-based linear regression models evaluated the correlation between log-transformed CSF values and PET biomarkers adjusting for age, sex, and diagnosis, when necessary.

“Voxel-based linear regression models evaluated the correlation between log transformed CSF values and PET biomarkers adjusting for age, sex, and diagnosis, when necessary.”

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

Both p-tau181 and p-tau217 Simoa assays demonstrated intra- and inter-assay variation <8%.

“Both methods demonstrated intra and inter assay variation <8%.”

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

The mean age of the population was 62.77 years, with CI participants being older than CU (CU = 59.82; CI = 67.78; P < 0.001) owing to a proportion of the CU being < 30 years.

“The mean age of the population was 62.77 years, with CI participants being older than CU (CU = 59.82; CI = 67.78; P < 0.001) owing to a proportion of the CU being < 30 years.”

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

APOE-ε4 carriers and males were more common in the CI group.

“APOE-ε4 carriers and males were also more common in the CI group.”

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

Linear regression models tested the association between log-transformed CSF p-tau and other biomarkers always adjusting by age and gender.

“Linear regression models also tested the association between log-transformed CSF p-tau and other biomarkers always adjusting by age and gender.”

May combine two claims.

CSF p-tau231 increases early in the development of AD pathology and its levels are raised earliest in preclinical AD.

“We demonstrate that CSF p-tau231 increases early in development of AD pathology”

• Also stated in: § Funding · hedged

  “Our novel finding suggests that CSF p-tau231 levels are raised earliest in preclinical AD.”

• AssumptionThe authors state this as an assumption: Aβ PET Centiloid values serve as a proxy of disease progression.
• AssumptionRests on an assumption: Cross-sectional differences in CSF p-tau and Aβ PET reflect the temporal ordering of biomarker changes in AD.

Classified as probably not a substantial claim.

Random field theory was used to correct the resulting t parametric maps for multiple comparisons (one-sided).

“Random field theory46 was used to correct the resulting t parametric maps for multiple comparisons (one-sided).”

• cites [46] Worsley, 2004, Unified univariate and multivariate random field theory, Neuroimage sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

NFTs, primarily composed of abnormal hyperphosphorylated tau, are a key pathological hallmark of AD.

“Neurofibrillary tangles (NFTs), primarily composed of abnormal hyperphosphorylated tau, are a key pathological hallmark of Alzheimer's disease (AD).”

• cites [1] Scheltens, 2016, Alzheimer's disease, Lancet sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Aβ PET positivity was visually defined by two neurologists blinded to clinical diagnosis.

“positivity was visually defined by two neurologists blinded to clinical diagnosis.”

May combine two claims.

The CI group had lower MMSE scores and higher Aβ PET and tau PET load compared to the CU group.

“As expected, the CI group had a lower MMSE scores, and higher Aβ PET and tau PET load as compared to the CU group (Table 1).”

May combine two claims.

CSF p-tau181 is not sensitive to early pathological changes but is an accurate biomarker at late-stage disease.

“No such changes were observed for other biomarkers demonstrating that CSF p-tau181 is not sensitive to early pathological changes but an accurate biomarker at late-stage disease.”

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

CSF p-tau biomarkers in this study are compared on two different platforms with differing detection and capture antibody configurations: N-terminally derived CSF p-tau181 and CSF p-tau217 on the Simoa platform, and Mid-terminal CSF p-tau231 by ELISA.

“CSF p-tau biomarkers in this study are compared on two different platforms, with differing detection and capture antibody configurations: N-terminally derived CSF p-tau181 and CSF p-tau217 on the Simoa platform, Mid-terminal CSF p-tau231 by ELISA.”

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

CSF p-tau, regardless of phosphorylation site, has been considered as a biomarker of NFT pathology, while other studies propose CSF p-tau as a state marker for brain tau phosphorylation, yet the direct association between CSF p-tau and tau PET has been inconsistent.

“CSF p-tau, regardless of phosphorylation site, has been considered as a biomarker of NFT pathology, while other studies propose CSF p-tau as a state marker for brain tau phosphorylation,62 yet the direct association between CSF p-tau and tau PET has been inconsistent.”

• cites [62] Blennow, 2003, CSF markers for incipient Alzheimer's disease, Lancet Neurol sourceNot checked — no full text of the source

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

Janelidze et al. previously described that CSF p-tau217 had a consistently greater regional association to tau PET than CSF p-tau181, but CSF p-tau231 was not analyzed in that study.

“In agreement to this, Janelidze et al. previously described that CSF p-tau217 had a consistently greater regional association to tau PET than CSF p-tau181 but CSF p-tau231 was not analyzed in this particular study.”

• cites Janelidze et al.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

CSF p-tau already changes with subtle Aβ pathology and occurs considerably earlier than previously anticipated.

“However, while it is presumed that p-tau secretion, and subsequent increase in CSF, occurs after globally aggregated Aβ, our data shows that CSF p-tau already changes with subtle Aβ pathology and therefore occurs considerably earlier than previously anticipated.”

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

The ADx253 antibody utilized in the p-tau231 ELISA was determined to simulate cis-selectivity, but the specific abundance of the toxic cis p-tau231 species in this assay format cannot be determined.

“In addition, the ADx253 antibody utilized in the p-tau231 ELISA was determined to simulate cis-selectivity however it cannot be determined the specific abundance of the toxic cis p-tau231 species in this assay format.”

May combine two claims.

CSF p-tau231 is a novel candidate for detecting early and emerging Aβ pathology in individuals for recruitment into therapeutic trials, as a target engagement biomarker to monitor the effect of Aβ therapeutics, or to support therapeutically targeting tau epitopes in preclinical disease before tau aggregation can be visualized by tau PET.

“Thus, CSF p-tau231 is a novel candidate for detecting early and emerging Aβ pathology in individuals for the recruitment into therapeutic trials, act as a target engagement biomarker to monitor the effect of Aβ therapeutics or supports the notion of therapeutically targeting tau epitopes in preclinical disease before tau aggregation can be visualized by tau PET.”

• AssumptionRests on an assumption: The pre-amyloid phase is the optimal period for therapeutic intervention.

May combine two claims.

The finding supports a model of active soluble tau release by cells into the CSF which is related to early Aβ deposition, likely induced by early Aβ seeds.

“This finding further supports a model of active soluble tau release by cells into the CSF which is related to early Aβ deposition, likely induced by early Aβ seeds.”

May combine two claims.

CSF p-tau231 could be a useful indicator of early Aβ deposition, with practical implications for highlighting early AD risk and enriching enrollment of individuals in the pre-amyloid phase in clinical trials.

“Consequently, CSF p-tau231 could be a useful indicator of early Aβ deposition, which can have practical implications for highlighting early AD risk and enrich the enrollment of individuals in the pre-amyloid phase in clinical trials.”

• AssumptionRests on an assumption: The pre-amyloid phase is the optimal period for therapeutic intervention.

May combine two claims.

As Aβ accumulates toward Aβ positivity, p-tau217 and p-tau181 become abnormal, with p-tau217 changing at a quicker rate.

“As Aβ accumulates toward Aβ positivity, other p-tau epitopes (p-tau217 and p-tau181) then become abnormal with p-tau217 changing at quicker rate.”

• AssumptionThe authors state this as an assumption: Aβ PET Centiloids can serve as a proxy of time/disease progression in AD.

May combine two claims.

Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD, and CSF p-tau231 is a stronger correlate to these early accumulating regions.

“This demonstrates that Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and our data reveals that CSF p-tau231 is a stronger correlate to these early accumulating regions.”

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

The main finding of early pre-amyloid changes of p-tau231 is based on 83 CU Aβ- individuals and should be replicated in an independent cohort not enriched for AD with exclusion criteria.

“Further to this, our main finding of early of pre-amyloid changes of p-tau231 is based on 83 CU Aβ- individuals and should be replicated in an independent cohort which is not enriched for AD with exclusion criteria's.”

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

The use of cross-sectional Aβ PET Centiloids as a proxy of time in the disease was employed, and it is not certain that a greater Aβ PET SUVR is indicative of a more advanced disease state.

“Furthermore, the use of cross‐sectional Aβ PET Centiloids as a proxy of time in the disease was employed and while a gradual Aβ accumulation is observed though AD development, it is not certain that a greater Aβ PET SUVR is indicative of more advanced disease state.”

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

It cannot be ruled out that subtle changes in biomarker performances are determined by platform differences or antibody superiority.

“Thus, it cannot be ruled out that subtle changes in biomarkers performances are determined by platform differences or antibody superiority.”