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, Les 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
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.