Broad non-AD clinical cohort coverage
The cohort includes 118 participants with DLB and 121 with FTLDr syndromes, extending ratio evaluation beyond the predominantly AD-focused prior literature.
↳ Materials and Methods, Clinical Cohort; Introduction
Abstract
INTRODUCTION: Neuronal pentraxin 2 (NPTX2) and its use as a ratio with other synaptic proteins has emerged as a prognostic cerebrospinal fluid (CSF) biomarker across neurodegenerative diseases.
METHODS: Using a single molecule array (Simoa) method, CSF NPTX2 was measured in 688 individuals from the Sant Pau Initiative on Neurodegeneration, including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration-related disorders (FTLDrs), and cognitively unimpaired (CU) participants. NPTX2/phosphorylated-tau (p-tau)181 performance was compared to standalone NPTX2 and p-tau181.
RESULTS: The NPTX2/p-tau ratio enhanced diagnostic performance of standalone NPTX2 and p-tau, particularly for DLB and FTLDrs (area under the curve [AUC]NPTX2/p-tau = 0.78-0.79 vs. AUCNPTX2 = 0.63-0.70 and AUCp-tau = 0.59-0.75), and was more strongly associated with cognition. It also better predicted progression to dementia across the cohort (hazard ratio [HR] = 1.63), especially in AD (HR = 1.84) and DLB (HR = 1.50).
DISCUSSION: NPTX2/p-tau may improve prognostic assessments in patients with cognitive impairment, outperforming standalone biomarkers.
Key Claims
Primary findingTentative
The NPTX2/p-tau ratio enhanced diagnostic performance of standalone NPTX2 and p-tau, particularly for DLB and FTLDrs.
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.
limited comparative design, with no significant DLB AUC improvement over p-tau and lower AD discrimination than p-tau
Abstract, Results; Figure 1D–F
SecondarySupported
The NPTX2/p-tau ratio was more strongly associated with cognition.
limited observational comparisons support several cognitive domains, although p-tau was stronger for memory and some visuospatial measures
Abstract; Results, Figure 2 and Table 2
SecondaryTentative
It also better predicted progression to dementia across the cohort, especially in AD and DLB.
limited single-cohort Cox analysis with incomplete follow-up and an internally impossible p-tau comparator interval
Abstract; Results, Figure 3 and Cox regression paragraph
Derived from the full evaluation — not a separate score.
Strengths · Limitations
Strengths
Blinded comparative biomarker analysis
Samples were blinded to clinical diagnosis and randomized before NPTX2 analysis, while AUC comparisons used DeLong tests and models adjusted for age, sex, and education.
↳ Materials and Methods, CSF Collection and Statistical Analysis
Multiple clinically relevant outcome domains
The study evaluates group separation, cognition, longitudinal GDS and MMSE, conversion to dementia, psychiatric features, and MRI associations within one cohort.
↳ Results, Figures 1–3; Tables 2–3; Figure S8
Limitations
Impossible progression comparator interval reported
The p-tau progression estimate is reported as HR 1.35 with a 95% CI of 0.57–0.97 and P < 0.05. This internally impossible combination directly affects the claim that the ratio predicted progression better than p-tau.
↳ Results, Cox regression paragraph; Figure 3
Superiority language exceeds reported comparisons
The DLB AUC for the ratio did not significantly exceed p-tau, while p-tau outperformed the ratio for AD discrimination. The abstract and conclusion nevertheless describe broad outperformance, particularly in DLB and FTLDrs.
↳ Abstract; Results, Figure 1D–F; Discussion, final paragraph
Follow-up selection remains unexamined
Only 57% of participants had longitudinal follow-up, and the article does not compare retained and non-retained participants or assess whether attrition relates to biomarkers, diagnosis, or cognition.
↳ Materials and Methods, Clinical Cohort; Discussion, limitations paragraph
Nabu Commentary
The study makes a useful incremental contribution by evaluating NPTX2/p-tau181 across AD, DLB, and FTLDr syndromes with broad cognitive and longitudinal outcomes. Its methods are generally competent, but longitudinal inference is weakened by 57% follow-up without a reported attrition analysis and by the absence of external validation. The abstract and conclusion overgeneralize comparative superiority because DLB discrimination did not significantly exceed p-tau and p-tau remained stronger for AD discrimination. Most importantly, the impossible p-tau HR confidence interval must be corrected before the progression comparison can be interpreted reliably.
Check another paper
Author Note / Field Feedback
Nabu’s assessment, alongside the field’s view.
Are you an author of this paper?
Dimension breakdown
Study Quality
Sound3.2
Confidence mediumContribution
3.3
The study incrementally extends NPTX2/p-tau181 evaluation beyond the AD continuum into sizeable DLB and FTLDr groups. Its advance is limited because superiority over standalone biomarkers is inconsistent and not established through joint-model or external-validation analyses.
Introduction; Results, Figure 1 and Cox regression paragraph
few studies have assessed the use of ratios with synaptic proteins
Methodological Rigour
3.0
Blinded and randomized biomarker measurement, adjusted models, DeLong tests, longitudinal ordering, and corrected imaging analyses support the design. Only 57% had follow-up, attrition was not characterized, and the p-tau HR/CI inconsistency remains a reliability concern.
Materials and Methods, Clinical Cohort and Statistical Analysis; Results, Figure 3
A subset (n = 391, 57%) had longitudinal follow-up
Reporting
3.3
The article follows a coherent progression from diagnostic separation to cognition and progression. Central outperformance language is too broad because DLB discrimination did not significantly exceed p-tau and p-tau remained superior for AD discrimination.
Abstract; Results, Figure 1D–F; Discussion, final paragraph
there was no difference in discriminatory power
Positioning
3.3
Prior NPTX2 and synaptic-ratio literature is discussed, and follow-up, FTLDr heterogeneity, pathology confirmation, and p-tau217 are identified as limitations or future work. Selection implications, biomarker-defined comparison groups, and absent external validation receive limited treatment.
Research in Context; Discussion, limitations paragraph
additional work in pathology-confirmed cohorts is needed
Reliability
Concerns4 of 4 checks
Internal CoherenceConcern
The dementia-progression comparator contains an internally impossible hazard-ratio confidence interval, and several lesser numerical or directional inconsistencies are present. The principal error bears directly on the claim that NPTX2/p-tau predicts progression better than standalone p-tau.
Research ConductNoted
Ethics approval, informed consent, and extensive conflicts are disclosed. A filed patent directly concerning synaptopathy markers is relevant to the promoted biomarker but is transparently reported.
Flags: 2 declared / 5 total
Reference IntegrityClean
37 references in manuscript 37 of 37 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.
Mechanistic
The study supplies single-cohort proof of concept rather than an implementation-ready test. The in-house assay has no externally validated cutoff, deployment guidance, or pathology-confirmed replication.
Materials and Methods, NPTX2 Measurements; Research in Context, Future Directions
using a recently developed in-house assay
AI-generated, human-governed. Something look off? Contact us to request a review.