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 Fougère, Christoph Laske, Jonathan Vöglein, Johannes Levin, Nick C. Fox, Natalie S. Ryan, Henrik Zetterberg, Jorge J. Llibre‐Guerra, Richard J. Perrin, Laura Ibáñez, Peter R. Schofield, William S. Brooks, Gregory S. Day, Martin R. Farlow, Ricardo Allegri, Patricio Chrem Méndez, 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, Stephanie A. Schultz, Dominantly Inherited Alzheimer Network, David Aguillón, Andrew J. Aschenbrenner, Bryce Baker, Nicolas R. Barthélemy, Randall J. Bateman, Jacob Bechara, Tammie L.S. Benzinger, Sarah Berman, David M. Cash, Allison Chen, Charles D. Chen, Jasmeer P. Chhatwal, Patricio Chrem Mendez, Laura Courtney, Carlos Cruchaga, Alisha Daniels, Gregory S. Day, Anne M. Fagan, Martin R. Farlow, Shaney Flores, Erin Franklin, Alison Goate, Susanne Gräber‐Sultan, Neill R. Graff‐Radford, Emily Gremminger, Jason Hassenstab, Elizabeth Herries, David M. Holtzman, Russ C. Hornbeck, Edward D. Huey, Snežana Ikonomović, Kelley Jackson, Steve Jarman, Gina Jerome, Erik C. B. Johnson, Nelly Joseph‐Mathurin, Celeste M. Karch, Sarah Keefe, Deborah Koudelis, Christoph Laske, Yudy Milena Leon, Allan I. Levey, Yan Li, Ruijin Lu, Jacob I. Marsh, Ralph N. Martins, Parinaz Massoumzadeh, Colin L. Masters, Austin McCullough, Eric McDade, Nicole S. McKay, Matthew Minton, John C. Morris, Neelesh K. Nadkarni, Joyce Nicklaus, Yoshiki Niimi, James M. Noble, Ulrike Obermueller, Danielle M. Picarello, Christine Pulizos, Laura Ramírez, Alan E. Renton, John M. Ringman, Jacqueline Rizzo
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.