Autopsy reference for central comparison
FTLD-tau and FTLD-TDP are defined neuropathologically, providing a strong reference standard for the headline disease comparison.
↳ Methods, Penn biomarker cohort participants
Abstract
Across tauopathies-Alzheimer's disease (AD), frontotemporal lobar degeneration due to tau (FTLD-tau)-we compared cerebrospinal fluid (CSF) biomarkers of phosphorylated-tau (p-tau) p-tau181, p-tau212, tau368, total tau (t-tau), and the tau368/t-tau ratio, and tested differentiation from non-tau (FTLD-TDP, neuronal α-synuclein disease (αSyn), and controls). In AD, CSF p-tau181 and p-tau212 were significantly higher than in all other groups, including FTLD-tau, while tau368/t-tau was significantly lower. With the aim to combine tau phosphorylation biomarkers (p-tau181 and p-tau212) with biomarkers for severity of tau pathology (tau368), we made ratios between these biomarkers and examined their diagnostic accuracy in FTLD after excluding high/intermediate AD neuropathologic change (ADNC). CSF p-tau181 and p-tau212, as well as p-tau181/tau368 and p-tau212/tau368, were higher in FTLD-tau compared with non-tau groups, and the diagnostic accuracy to discriminate FTLD-tau from FTLD-TDP improved. Levels of the ratios were increased in behavioral and primary progressive aphasia variants of tauopathies when compared to FTLD-TDP. Furthermore, the biomarkers showed significant correlation with both FTLD-tau and AD tau burden at autopsy across brain regions. These results suggest unique patterns of increased relative levels of p-tau epitopes in CSF among ADNC and FTLD-tau could improve the diagnosis of tauopathies and inform inclusion criteria in clinical trial design.
Key Claims
Primary findingTentative
CSF p-tau181 and p-tau212, as well as p-tau181/tau368 and p-tau212/tau368, were higher in FTLD-tau compared with non-tau groups, and the diagnostic accuracy to discriminate FTLD-tau from FTLD-TDP improved.
Fragile — the claim's weakest requirement is that the effect exists at all. Experimental. Every point below is traceable to a quoted passage, but this forecast has not yet been validated against known replication outcomes.
small retrospective subgroups, post hoc PSP exclusion, and inconsistent AUC reporting limit the claimed incremental accuracy
Abstract; Results, FTLD ROC analysis
SecondaryWell-supported
In AD, CSF p-tau181 and p-tau212 were significantly higher than in all other groups, including FTLD-tau, while tau368/t-tau was significantly lower.
autopsy-defined AD comparisons and reported group medians consistently support the stated biomarker pattern
Abstract; Results, AD biomarker comparisons; Table 1
SecondaryTentative
Levels of the ratios were increased in behavioral and primary progressive aphasia variants of tauopathies when compared to FTLD-TDP.
very small bvFTD groups and supplementary PPA analyses limit clinical-subtype inference
Abstract; Results, clinical variants; Fig. 5
SecondaryTentative
the biomarkers showed significant correlation with both FTLD-tau and AD tau burden at autopsy across brain regions.
small exploratory correlations and incomplete within-FTLD significance limit the breadth of the statement
Abstract; Results, brain tau correlation sections
Derived from the full evaluation — not a separate score.
Strengths · Limitations
Strengths
Addresses an unmet biomarker need
The study targets the absence of reliable fluid biomarkers for FTLD-tau and connects the proposed markers to clinical-trial selection and differentiation of overlapping syndromes.
↳ Introduction, paragraph 1; Conclusions
Multiple safeguards in quantitative analysis
The analysis reports assay precision, FDR correction, bootstrap confidence intervals, and blinded case-level image quantification.
↳ Methods, Biomarker measurements; Microscopy; Statistical analyses
Limitations
Central AUC reporting does not reconcile
The Results and Discussion report materially different AUCs for FTLD-tau versus FTLD-TDP, changing the apparent size of tau368’s incremental benefit.
↳ Results, FTLD ROC analysis; Discussion, FTLD diagnostic-performance paragraph
PSP exclusion is outcome informed
Four PSP cases were removed from the main ADNC-negative analysis after being identified as tau368-ratio outliers, while analyses retaining them appear only in supplementary material.
↳ Results, “CSF p-tau/tau368 ratios improve the diagnostic accuracy…”, paragraph 1
Clinical claims exceed validation stage
The Conclusions predict fewer false results and improved diagnosis despite a small, single-biobank proof-of-concept cohort with no external validation.
↳ Discussion, limitations paragraph; Conclusions
Nabu Commentary
The autopsy-defined FTLD comparison and rare paired CSF–pathology material support a meaningful early contribution. Methodological credit is tempered by the post hoc removal of PSP cases based on tau368-ratio behaviour, small FTLD subgroups, and lack of external validation. The principal reporting problem is that the Results and Discussion provide different AUCs for the same central comparisons, while the manuscript also calls a p=0.057 correlation significant and invokes mediation without a mediation analysis. The limitations section appropriately describes the work as initial validation, but the Conclusions make stronger claims about improved diagnosis and reduced false results.
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Author Note / Field Feedback
Nabu’s assessment, alongside the field’s view.
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Dimension breakdown
Study Quality
Limited2.9
Confidence mediumContribution
3.2
The study tests p-tau/tau368 ratios against autopsy-defined FTLD pathology in a setting with no established fluid biomarker, providing a genuine but preliminary advance. Incremental value is clearest for p-tau181 and is limited by small subgroups and inconsistent performance reporting.
Introduction; Results, FTLD ROC analysis; Discussion, FTLD diagnostic-performance paragraph
there are no robust and reliable fluid biomarkers specific to FTLD-tau
Methodological Rigour
2.6
Autopsy reference diagnoses, assay precision, bootstrap AUC intervals, multiplicity correction, and blinded image quantification support the design. Methodological Rigour is constrained by the pathology-enriched spectrum, post hoc PSP exclusion, internally selected Youden cutpoints, unreported assay/pathology blinding, and unreconciled central analysis counts.
Methods, Penn biomarker cohort and Statistical analyses; Results, FTLD diagnostic-performance section
Analyses revealed that FTLD-tau PSP cases were outliers for tau368 ratio levels
Reporting
2.7
The question-to-analysis sequence is followable, but central AUCs differ between the Results and Discussion and sensitivity improvement is claimed without corresponding sensitivity estimates. The mediation and significant-correlation wording also exceeds the reported analysis.
Results, FTLD ROC analysis and “Tau368 mediates…”; Discussion, FTLD diagnostic-performance paragraph
CSF tau368 was negatively correlated with tau burden, although this did not reach significance
Positioning
3.2
The paper engages prior p-tau, MTBR-tau, PSP, and FTLD biomarker findings and explicitly acknowledges limited generalizability and the need for replication. Positioning remains below the stronger band because the Conclusions make clinical-improvement claims stronger than the proof-of-concept evidence supports.
Discussion, PSP discussion and limitations paragraph; Conclusions
replication and extension will be required before these assays can be applied for widespread clinical use
Reliability
Concerns4 of 4 checks
Internal CoherenceConcern
Central diagnostic-performance reporting is not internally consistent, and the primary FTLD analysis uses a post hoc, index-test-informed PSP exclusion. These issues materially affect the claimed incremental value of tau368 normalization.
Research ConductClean
Ethics approval and informed consent are declared for both cohorts. No supplied-text evidence establishes a research-conduct concern; absent conflict, data, code, or registration statements are treated as reporting or assessability gaps rather than misconduct signals.
Flags: 1 declared / 5 total
Reference IntegrityClean
126 references in manuscript 126 of 126 checkable references found in an index
Post-Publication RecordClean
No retraction notice found in Retraction Watch.
Last checked: 08 Oct 2026
Sources: Retraction Watch ✓
Readiness
Where this paper’s evidence sits on the path from initial observation to real-world use.
Demonstrated
The work is an initial autopsy-anchored validation of CSF assays rather than an operational clinical validation. Larger replicated cohorts, early-stage testing, and plasma comparisons are identified as necessary next steps.
Discussion, limitations paragraph
we emphasize this is important initial validation work
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