Comparative neurofilament light chain trajectories in CSF and plasma in autosomal dominant Alzheimer’s disease
Authors: Hofmann Anna , Häsler Lisa M. , Lambert Marius , Kaeser Stephan A. , Gräber-Sultan Susanne , Obermüller Ulrike , Kuder-Buletta Elke , la Fougere Christian , Laske Christoph , Vöglein Jonathan , Levin Johannes , Fox Nick C. , Ryan Natalie S. , Zetterberg Henrik , Llibre-Guerra Jorge J. , Perrin Richard J. , Ibanez Laura , Schofield Peter R. , Brooks William S. , Day Gregory S. , Farlow Martin R. , Allegri Ricardo F. , Chrem Mendez Patricio , Ikeuchi Takeshi , Kasuga Kensaku , Lee Jae-Hong , Roh Jee Hoon , Mori Hiroshi , Lopera Francisco , Bateman Randall J. , McDade Eric , Gordon Brian A. , Chhatwal Jasmeer P. , Jucker Mathias , Schultz Stephanie A. ,   Dominantly Inherited Alzheimer Network, Aguillon David , Aschenbrenner Andrew J. , Baker Bryce , Barthelemy Nicolas , Bateman Randall , Bechara Jacob A. , Benzinger Tammie , Berman Sarah B. , Cash David M. , Chen Allison , Chen Charles , Chhatwal Chhatwal Jasmeer P. , Mendez Patricio Chrem , Courtney Laura , Cruchaga Carlos , Daniels Alisha J. , Day Gregory S. , Fagan Anne M. , Farlow Martin , Flores Shaney , Franklin Erin , Goate Alison M. , Graber-Sultan Susanne , Graff-Radford Neill R. , Gremminger Emily , Hassenstab Jason , Herries Elizabeth , Holtzman David M. , Hornbeck Russ , Huey Edward D. , Ikonomovic Snezana , Jackson Kelley , Jarman Steve , Jerome Gina , Johnson Erik C. B. , Joseph-Mathurin Nelly , Karch Celeste M. , Keefe Sarah , Koudelis Deborah , Laske Christoph , Leon Yudy Milena , Levey Allan I. , Li Yan , Lu Ruijin , Marsh Jacob , Martins Ralph , Massoumzadeh Parinaz , Masters Colin , McCullough Austin , McDade Eric , McKay Nicole , Minton Matthew , Morris John C. , Nadkarni Neelesh K. , Nicklaus Joyce , Niimi Yoshiki , Noble James M. , Obermueller Ulrike , Picarello Danielle M. , Pulizos Christine , Ramirez Laura , Renton Alan E. , Ringman John , Rizzo Jacqueline , Roedenbeck Yvonne , Rosa-Neto Pedro , Sabaredzovic Edita , Salloway Stephen , Sanchez-Valle Raquel , Scott Jalen , Seyfried Nicholas T. , Simmons Ashlee , Smith Jennifer , Smith Hunter , Stauber Jennifer , Stout Sarah , Supnet-Bell Charlene , Surace Ezequiel , Vazquez Silvia , Vöglein Jonathan , Wang Guoqiao , Wang Qing , Xiong Chengie , Xu Xiong , Xu Jinbin 
Published: November 2024

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.