The use of cerebrospinal fluid biomarkers to measure change in neurodegeneration in Alzheimer’s disease clinical trials

ABSTRACT

Introduction: All recent phase 3 trials of potentially disease-modifying therapies for Alzheimer’s disease (AD) have so far failed. Potential reasons include enrolling subjects whose disease is too advanced or who do not have AD pathology, or simply incorrect drug targets. The goal of disease-modifying AD trials is to halt the progress of neuronal damage and death and this can be assessed in vivo using cerebrospinal fluid (CSF) biomarkers.

Areas covered: The authors conducted a literature search of the use of CSF biomarkers in disease-modifying AD clinical trials using PubMed. The authors show that CSF biomarkers have only sparsely been used as outcome measures, and where they have, only in small subsets of patients. No clinical trials have yet showed any substantial effects on CSF biomarkers of neurodegeneration.

Expert commentary: In future trials, the authors advocate that CSF biomarkers be used more extensively to optimize the chance of detecting positive drug effects. This includes the identification of potential AD patients – already in the early prodromal stage – for inclusion, for stratification, as readout i.e. proximity markers for changes in axonal/neurodegeneration between treatment and placebo groups – this also enables proof of principle verification in the discovery/dose finding phase, and for monitoring of side effects.

KEYWORDS:

• CSF
• biomarkers
• clinical trial
• Alzheimer’s disease
• neurodegeneration

Declaration of interest

J.M. Schott reports personal fees from Roche and Eli Lilly, grants and non-financial support from AVID Radiopharmaceuticals, and serves on a data safety management board for Axon Neuroscience. K. Blennow has served as advisory boards for Roche Diagnostics and IBL International and is a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures–based platform company at the University of Gothenburg. H. Zetterberg is co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg, and has served at advisory boards for Roche Diagnostics, Eli Lilly and Pharmasum Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The work in the authors’ laboratories is funded by the Swedish Research Council and European Research Council, the Wolfson Foundation, the Knut and Alice Wallenberg Foundation, Swedish State Support for Clinical Research and the Torsten Söderberg Foundation.​​​