Researchers at the Alzheimer Center Amsterdam (Amsterdam UMC) have published a study on a novel cerebrospinal fluid biomarker, AcTau174, in Nature Medicine. In this study, neuroscientists Madison Honey, Charlotte Teunissen, and colleagues show that AcTau174 concentrations are elevated across multiple neurodegenerative diseases, including two forms of frontotemporal dementia (FTD), Alzheimer’s disease (AD), mild cognitive impairment due to AD (MCI-AD), and dementia with Lewy bodies (DLB). Importantly, they demonstrate that AcTau174 concentrations can differentiate between underlying pathologies in FTD. These findings may contribute to more targeted diagnostics and improved patient selection for clinical trials.

Addressing a long-standing challenge in FTD research

A major challenge in FTD research and clinical trials is the ability to distinguish between two underlying types of frontotemporal lobar degeneration: FTLD-tau and FTLD-TDP. Currently, there are limited biomarkers that can reliably differentiate these pathologies during life. To address this, a team at the Alzheimer Center Amsterdam, including Honey, Teunissen, and Hok-A-Hin, developed an ultrasensitive immunoassay to quantify acetylated tau at lysine 174 (AcTau174) in cerebrospinal fluid. They showed that concentrations of this biomarker can distinguish between patients with FTLD-tau and FTLD-TDP.

Unexpected findings in cerebrospinal fluid

The study was not originally designed to investigate FTD, but rather focused on biomarkers for Alzheimer’s disease. During the analysis, the researchers made an unexpected observation: instead of higher levels in patients with tau pathology, AcTau174 concentrations were significantly higher in patients with TDP-43 pathology than in those with FTLD-tau or in controls. This finding was surprising, but proved to be robust and consistent across analyses.

Validation in international cohorts

The results were first identified in the Amsterdam Dementia Cohort and subsequently replicated in two independent international cohorts. AcTau174 showed good performance in distinguishing FTLD-TDP from FTLD-tau, supporting its potential as a diagnostic biomarker.

Evidence for prognostic value

In addition, higher AcTau174 levels were also associated with more severe disease and faster cognitive decline in patients with TDP-43 pathology. This suggests that the biomarker may have not only diagnostic but also prognostic value.

Differences between cerebrospinal fluid and brain tissue

Notably, in postmortem brain tissue, higher levels of AcTau174 were observed in FTD patients with tau pathology or Alzheimer’s disease, whereas the concentration in cerebrospinal fluid was higher in FTD patients with TDP-43. This suggests that soluble and insoluble forms of tau may behave differently in various disease processes.

Implications for diagnosis and research

The researchers conclude that AcTau174 is a promising biomarker for distinguishing between TDP-43 and tau pathology in FTD during a patient’s lifetime. This could be important for diagnosis, prognosis, and the targeted inclusion of patients in future treatment studies. Further studies are needed to determine how this marker can best be utilized in clinical practice.

Read the publication in Nature Medicine: An acetylated Tau-174 CSF biomarker discriminates between TDP-43 and tau pathology in patients with frontotemporal lobar degeneration

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