CSF Tau and Amyloid Biomarkers in Cognitive Impairment Across the ALS-FTD Spectrum: A Systematic Narrative Review and Evidence Map.

Authors

Aasim Ali, Muhammad Arif, Usama Ashraf, Saad Elahi, Aswad Mustafa, Mahad Bin Yasir, Waqar Sarfraz, Asad Ullah Ansari, Hafiz Muhammad Yousaf Masood, Muhammad Asad Shabbir, Armaghana Abdullah, Mukesh Kumar Sharma

Published in

Brain and behavior. Volume 16. Issue 9. Pages e71740.

Abstract

Cognitive impairment is an important non-motor manifestation of amyotrophic lateral sclerosis (ALS), particularly across the ALS-frontotemporal dementia (ALS-FTD) spectrum. Cerebrospinal fluid (CSF) tau and amyloid biomarkers may reflect nonspecific neurodegenerative injury, concomitant Alzheimer disease (AD) pathology, or distinct cognitive phenotypes. However, available evidence remains limited, fragmented, and methodologically heterogeneous.
This systematic narrative review and semi-quantitative evidence map was conducted according to PRISMA 2020 recommendations. PubMed, Scopus, Web of Science, and Google Scholar were searched from database inception through May 2026. Eligible observational studies reported cognition-specific associations between CSF tau, amyloid, or related neurodegenerative biomarkers and cognitive outcomes in ALS-spectrum populations. Two reviewers independently screened studies, extracted quantitative effect estimates, and assessed risk of bias using the Newcastle-Ottawa Scale. Cross-study consistency was summarized using an exploratory semi-quantitative evidence-coding framework.
Four observational studies comprising 638 ALS-spectrum participants fulfilled the eligibility criteria. Total tau and p-tau181 showed the most reproducible associations with cognition. Total tau correlated with ECAS total (r = -0.398, P < 0.001) and ALS-specific cognition (r = -0.403, P < 0.001), while adjusted multicenter analyses demonstrated associations between p-tau181 and ECAS total (β = -0.03, p = 0.006) and memory performance (β = -0.04, p = 0.003). Both biomarkers received ++ evidence-map coding. Amyloid findings were more heterogeneous; lower Aβ42/Aβ40 was associated with poorer memory performance (β = 0.20, p = 0.044), but continuous amyloid-cognition associations were not consistently replicated across cohorts (± evidence). Broader CSF protein-ratio findings remained exploratory. Clinical, cognitive, assay, and analytical heterogeneity precluded meta-analysis.
The available evidence, although limited and heterogeneous, suggests that total tau may primarily reflect broader neurodegenerative injury, whereas p-tau181 and Aβ42/Aβ40 may be more informative for selected cognitive phenotypes or possible AD co-pathology. These biomarkers should remain research tools until larger, standardized, longitudinal multicenter studies establish their pathological specificity, predictive value, and clinical utility.

PMID:
42677779
Bibliographic data and abstract were imported from PubMed on 01 Sep 2026.

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