An acetylated Tau-174 CSF biomarker discriminates between TDP-43 and tau pathology in patients with frontotemporal lobar degeneration

Biomarkers to determine underlying frontotemporal lobar degeneration (FTLD) tau or TAR DNA-binding protein (TDP) pathology during life are needed to advance clinical trials targeting specific FTD pathologies. For this purpose, we developed a new ultrasensitive immunoassay to quantify acetylated tau at lysine 174 (AcTau174) in cerebrospinal fluid (CSF). In a sporadic cohort (n = 513), AcTau174 concentrations were higher in all dementia groups (FTLD-TDP, FTLD-Tau, Alzheimer's disease (AD), mild cognitive impairment (MCI)-AD and dementia with Lewy bodies (DLB)) compared to controls. The largest increase was observed in the FTLD-TDP group, particularly patients with semantic variant primary progressive aphasia (svPPA) and GRN mutation carriers. Notably, AcTau174 discriminated FTLD-TDP from FTLD-Tau (area under the curve (AUC) = 0.83, 95% confidence interval (CI) = 0.75-0.91) and FTLD-TDP from controls (AUC = 0.95, 95% CI = 0.92-0.99) with high accuracy. This was replicated in independent, sporadic and genetic validation cohorts (164 patients and 24 controls), albeit with somewhat lower accuracy (FTLD-TDP versus FTLD-Tau; AUC range = 0.75-0.79) and wider CIs. Within the FTLD-TDP, AD and MCI-AD groups, higher AcTau174 concentrations were associated with a faster cognitive decline over time. In summary, CSF AcTau174 has great potential to discriminate FTLD-TDP from FTLD-Tau as a biomarker reflecting FTLD-TDP disease severity and progression.

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Journal
Nature Medicine
Published
2026-04-15
DOI
https://doi.org/10.1038/s41591-026-04341-6
Primary Topic
Dementia and Cognitive Impairment Research
Type
article
Field-Weighted Citation Impact
0.00

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article

An acetylated Tau-174 CSF biomarker discriminates between TDP-43 and tau pathology in patients with frontotemporal lobar degeneration

Yanaika S. Hok‐A‐Hin, Juan Fortea, Alberto Lleó, Flora H. Duits et al.
Nature Medicine
Dementia and Cognitive Impairment Research
article

An acetylated Tau-174 CSF biomarker discriminates between TDP-43 and tau pathology in patients with frontotemporal lobar degeneration

Yanaika S. Hok‐A‐Hin, Juan Fortea, Alberto Lleó, Flora H. Duits, Adam L. Boxer, Katheryn A Q Cousins, Wiesje M. van der Flier, Erik Stoops, Harro Seelaar, Elisabeth H. Thijssen, Edward B. Lee, Inge M.W. Verberk, Emma van der Ende, Madison I. J. Honey, Charlotte Elisabeth Teunissen, David J. Irwin, Tjado H. J. Morrema, Julie F. H. De Houwer, Les Shaw, Babette van der Weijden, Jeroen J. M. Hoozemans, Li Gan, Ignacio Illán-Gala, Daniel Alcolea, Lisanne in ‘t Veld, Yolande Pijnenburg, Sterre C. M. de Boer, Corey T. McMillan, David A. Wolk
article en

Abstract

Biomarkers to determine underlying frontotemporal lobar degeneration (FTLD) tau or TAR DNA-binding protein (TDP) pathology during life are needed to advance clinical trials targeting specific FTD pathologies. For this purpose, we developed a new ultrasensitive immunoassay to quantify acetylated tau at lysine 174 (AcTau174) in cerebrospinal fluid (CSF). In a sporadic cohort (n = 513), AcTau174 concentrations were higher in all dementia groups (FTLD-TDP, FTLD-Tau, Alzheimer's disease (AD), mild cognitive impairment (MCI)-AD and dementia with Lewy bodies (DLB)) compared to controls. The largest increase was observed in the FTLD-TDP group, particularly patients with semantic variant primary progressive aphasia (svPPA) and GRN mutation carriers. Notably, AcTau174 discriminated FTLD-TDP from FTLD-Tau (area under the curve (AUC) = 0.83, 95% confidence interval (CI) = 0.75-0.91) and FTLD-TDP from controls (AUC = 0.95, 95% CI = 0.92-0.99) with high accuracy. This was replicated in independent, sporadic and genetic validation cohorts (164 patients and 24 controls), albeit with somewhat lower accuracy (FTLD-TDP versus FTLD-Tau; AUC range = 0.75-0.79) and wider CIs. Within the FTLD-TDP, AD and MCI-AD groups, higher AcTau174 concentrations were associated with a faster cognitive decline over time. In summary, CSF AcTau174 has great potential to discriminate FTLD-TDP from FTLD-Tau as a biomarker reflecting FTLD-TDP disease severity and progression.

Nature Medicine
The University of Sydney (AU), University of California, San Francisco (US), Cornell University (US), Hospital de Sant Pau (ES), Erasmus MC (NL), UNSW Sydney (AU), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), MIND Research Institute (US), Amsterdam Neuroscience (NL), Alzheimer Nederland (NL), Amsterdam University Medical Centers (NL), ADx NeuroSciences (BE), ADx NeuroSciences, University of Pennsylvania (US), Vrije Universiteit Amsterdam (NL)
Alzheimer's Drug Discovery Foundation
Reduced inequalities
Openalex Percentile: Top 24%
Dementia and Cognitive Impairment Research
DOIOpen Access PDFOpenAlex
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