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<p>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 (<i>n</i> = 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 <i>GRN</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月15日

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

摘要

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.