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Phosphorylated tau181 (p-tau181), an Alzheimer's disease biomarker, was recently evaluated in amyotrophic lateral sclerosis (ALS). We investigated plasma p-tau181 in 202 ALS/ALS-FTD patients and 94 healthy controls, assessing cognitive performance, motor function, and longitudinal dynamics. Plasma p-tau181 and NfL were significantly elevated in ALS, with p-tau181 increasing over 1 year while NfL remained stable. Neither marker correlated with cognitive performance, and only NfL was associated with disease severity and progression. Plasma p-tau181 was higher in patients with predominant lower motor neuron involvement. The results indicate that p-tau181 reflects peripheral processes in ALS, providing a complementary, mechanistically distinct biomarker from NfL.
The results indicate that p-tau181 reflects peripheral processes in ALS, providing a complementary, mechanistically distinct biomarker from NfL.
the observational associations and null findings cannot identify biological source or establish mechanistic distinction
Plasma p-tau181 and NfL were significantly elevated in ALS, with p-tau181 increasing over 1 year while NfL remained stable.
reported group comparisons and longitudinal interaction support the direction, but retention and longitudinal sample details are not summarized
Neither marker correlated with cognitive performance.
age-adjusted corrected correlations were null, but the analysis does not establish equivalence or exclude measurement attenuation
only NfL was associated with disease severity and progression.
reported cohort associations support the contrast, though prognostic evidence is observational and conflicts with other cohorts
Plasma p-tau181 was higher in patients with predominant lower motor neuron involvement.
a significant subgroup comparison supports the direction, but subgroup size and independent replication are not reported here
Derived from the full evaluation — not a separate score.
Strengths
The study evaluates cognition, motor phenotype, clinical course, and one-year biomarker dynamics in the same research program, adding an integrated perspective beyond a single cross-sectional comparison.
↳ Introduction; Results, paragraphs 2–5; Figures 1–5
Plasma p-tau181 was measured in technical duplicate with an acceptance threshold and inter-run control, while NfL measurement was blinded. Cognitive correlations controlled for age and multiple comparisons.
↳ Methods, paragraphs 2–5
The Discussion identifies the discordant NULISA study and other prognostic reports rather than presenting the literature as uniform, while noting that severity associations need further investigation.
↳ Discussion, paragraph 3
Limitations
Null cognitive and CSF associations plus one LMN subgroup contrast cannot establish that plasma p-tau181 originates peripherally. The Abstract and Conclusion nevertheless make this the central mechanistic interpretation.
↳ Abstract, final sentence; Discussion, paragraphs 1 and 3; Conclusion
The cognition and severity nulls are reported without power analysis, equivalence testing, or discussion of attenuation from assay and screening measurement error. This limits claims of absence rather than non-detection.
↳ Methods, paragraphs 2–5; Results, paragraphs 3–4
The Discussion acknowledges unavailable survival data but does not state that peripheral source was not directly measured. It also proposes therapy-response value without treatment-response observations.
↳ Discussion, paragraph 3; Conclusion
The descriptive findings are supported by standardized clinical assessment, assay quality controls, corrected correlations, and longitudinal mixed-effects analysis. The integrated cognitive, phenotype, and longitudinal evaluation represents a meaningful but incremental extension of prior ALS p-tau181 research. The central score constraint is the inference that p-tau181 has a peripheral source, which the observational associations and non-associations cannot identify. The same limitation is not adequately carried into the Discussion and Conclusion, where mechanistic distinction and possible therapy-response utility are stated too strongly.
Nabu’s assessment, alongside the field’s view.
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Confidence mediumThe study combines cognition, motor phenotype, ATN/APOE comparisons, NfL benchmarking, and one-year change in two multicentre cohorts. This meaningfully extends a small literature, although elevated p-tau181 and its LMN association partly replicate earlier reports.
“We further investigated longitudinal dynamics of plasma p‐tau181 in relation to NfL”
Duplicate assays, inter-run control, blinded NfL measurement, age-adjusted correlations, multiplicity correction, and mixed-effects models support the descriptive analyses. The observational design cannot identify a peripheral source, and uncertainty around null findings, attrition, missingness, and measurement attenuation is not adequately resolved.
“supporting a peripheral rather than cerebral source”
The article follows a coherent sequence from biomarker rationale through cognitive, motor, and longitudinal results. Its Abstract and Conclusion nevertheless convert an indirect pattern into a comparatively firm peripheral-source and mechanistic-distinction claim.
“providing a complementary, mechanistically distinct biomarker from NfL”
The Discussion engages prior ALS p-tau181 studies, including the discordant NULISA result, and acknowledges unavailable survival data. It does not explicitly acknowledge that the study lacks direct evidence capable of identifying p-tau181’s biological source.
“The correlation to severity needs further investigations.”
Caveats4 of 4 checks
Reported numerical findings are broadly consistent across the Abstract, Results, and Discussion, but two interpretation-level coherence issues warrant caution. Neither issue indicates that the reported numerical results are fabricated or statistically impossible.
Ethics approval and conflicts are explicitly declared, with no location-referenced evidence of misconduct. Independent verification is limited because anonymized data and scripts are available only upon reasonable request.
Flags: 4 declared / 5 total
21 references in manuscript 21 of 21 checkable references found in an index
No retraction notice found in Retraction Watch.
Sources: Retraction Watch ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
The work remains at observational biomarker-characterization stage and reports no clinical threshold, treatment-response analysis, external validation, or implementation pathway. Its findings can motivate further studies but are not action-ready.
“it may represent a valuable additional biomarker of therapy response”
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