Comparative neurofilament light chain trajectories in CSF and plasma in autosomal dominant Alzheimer’s disease

Anna Hofmann, Lisa M. Häsler, Marius Lambert, Stephan A. Kaeser, Susanne Gräber-Sultan, Ulrike Obermüller, Elke Kuder-Buletta, Christian la Fougere, Christoph Laske, Jonathan Vöglein, Johannes Levin, Nick C. Fox, Natalie S. Ryan, Henrik Zetterberg, Jorge J. Llibre-Guerra, Richard J. Perrin, Laura Ibanez, Peter R. Schofield, William S. Brooks, Gregory S. Day, Martin R. Farlow, Ricardo F. Allegri, Patricio Chrem Mendez, Takeshi Ikeuchi, Kensaku Kasuga, Jae-Hong Lee, Jee Hoon Roh, Hiroshi Mori, Francisco Lopera, Randall J. Bateman, Eric McDade, Brian A. Gordon, Jasmeer P. Chhatwal, Mathias Jucker () and Stephanie A. Schultz ()
Additional contact information
Anna Hofmann: German Center for Neurodegenerative Diseases (DZNE)
Lisa M. Häsler: German Center for Neurodegenerative Diseases (DZNE)
Marius Lambert: German Center for Neurodegenerative Diseases (DZNE)
Stephan A. Kaeser: German Center for Neurodegenerative Diseases (DZNE)
Susanne Gräber-Sultan: German Center for Neurodegenerative Diseases (DZNE)
Ulrike Obermüller: German Center for Neurodegenerative Diseases (DZNE)
Elke Kuder-Buletta: German Center for Neurodegenerative Diseases (DZNE)
Christian la Fougere: German Center for Neurodegenerative Diseases (DZNE)
Christoph Laske: German Center for Neurodegenerative Diseases (DZNE)
Jonathan Vöglein: German Center for Neurodegenerative Diseases (DZNE)
Johannes Levin: German Center for Neurodegenerative Diseases (DZNE)
Nick C. Fox: UCL Queen Square Institute of Neurology
Natalie S. Ryan: UCL Queen Square Institute of Neurology
Henrik Zetterberg: the Sahlgrenska Academy at the University of Gothenburg
Jorge J. Llibre-Guerra: Washington University School of Medicine
Richard J. Perrin: Washington University School of Medicine
Laura Ibanez: Washington University School of Medicine
Peter R. Schofield: Neuroscience Research Australia
William S. Brooks: Neuroscience Research Australia
Gregory S. Day: Mayo Clinic in Florida
Martin R. Farlow: Indiana University School of Medicine
Ricardo F. Allegri: Instituto Neurológico FLENI
Patricio Chrem Mendez: Instituto Neurológico FLENI
Takeshi Ikeuchi: Niigata University
Kensaku Kasuga: Niigata University
Jae-Hong Lee: Asan Medical Center
Jee Hoon Roh: Korea University College of Medicine
Hiroshi Mori: Nagaoka Sutoku University
Francisco Lopera: Universidad de Antioquia
Randall J. Bateman: Washington University School of Medicine
Eric McDade: Washington University School of Medicine
Brian A. Gordon: Washington University School of Medicine
Jasmeer P. Chhatwal: Harvard Medical School
Mathias Jucker: German Center for Neurodegenerative Diseases (DZNE)
Stephanie A. Schultz: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Disease-modifying therapies for Alzheimer’s disease (AD) are likely to be most beneficial when initiated in the presymptomatic phase. To track the benefit of such interventions, fluid biomarkers are of great importance, with neurofilament light chain protein (NfL) showing promise for monitoring neurodegeneration and predicting cognitive outcomes. Here, we update and complement previous findings from the Dominantly Inherited Alzheimer Network Observational Study by using matched cross-sectional and longitudinal cerebrospinal fluid (CSF) and plasma samples from 567 individuals, allowing timely comparative analyses of CSF and blood trajectories across the entire disease spectrum. CSF and plasma trajectories were similar at presymptomatic stages, discriminating mutation carriers from non-carrier controls 10-20 years before the estimated onset of clinical symptoms, depending on the statistical model used. However, after symptom onset the rate of change in CSF NfL continued to increase steadily, whereas the rate of change in plasma NfL leveled off. Both plasma and CSF NfL changes were associated with grey-matter atrophy, but not with Aβ-PET changes, supporting a temporal decoupling of Aβ deposition and neurodegeneration. These observations support NfL in both CSF and blood as an early marker of neurodegeneration but suggest that NfL measured in the CSF may be better suited for monitoring clinical trial outcomes in symptomatic AD patients.

Date: 2024
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DOI: 10.1038/s41467-024-52937-8

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