- April 1, 2026
- Laura Ibanez, et al., Washington University, St. Louis
Topic/Product:
CNS Disease Panel 120
Disease Area:
Alzheimer's Disease
Sample Type:
CSF
Abstract
BACKGROUND Increasing evidence suggests that accurate prediction of Alzheimer’s disease (AD) symptom onset requires more than amyloid- and tau-centric biomarkers such as cerebrospinal fluid (CSF) Aβ42/40, total tau and p-tau181 and plasma p-tau217. Autosomal dominant AD (ADAD), caused by pathogenic PSEN1, PSEN2 and APP mutations with predictable age at symptom onset, presents a unique opportunity to characterize the chronological changes in proteins beyond amyloid and tau and clarify them as early biomarkers of disease onset or as biomarkers related to disease staging and progression monitoring.
METHODS We measured 972 CSF samples corresponding to 484 participants of the Dominantly Inherited Alzheimer Disease Network (DIAN) using the NULISASeq 120 CNS Disease Panel. We first benchmarked the technology against gold-standard measurements followed by the identification of proteins that were differentially abundant in relation to mutation status and symptomatology. Next, we determined the chronological emergence of protein changes in relation to the estimated years to onset (EYO). Finally, we assessed whether specific protein measures improved the prediction of EYO in the ADAD.
FINDINGS NULISA measurements were comparable to those previously published. We demonstrated that known early alterations in CSF amyloid and tau were followed by inflammatory and neurodegenerative responses suggesting that clinical manifestation of AD happens before the inflammatory processes is fully developed. Finally, we found a multi-protein composite approach for predicting EYO that outperformed single biomarker values.
INTERPRETATION Our results suggest that the main CSF proteomic landscape changes in ADAD are due to the presence of a pathogenic mutation and occur prior to symptom onset. Improved performance of multi-protein composite to predict EYO compared to single biomarker values highlights the added value of multiplex proteomic signatures for biomarker panel development.
Authors & Affiliations
Wenjing Lin* ¹², Aleksandra Beric* ¹², Julie K. Wisch³, Bryce Baker¹, Gina Jerome¹, Matthew Minton¹, Sam Preminger¹, Jennifer Stauber¹, Suzanne E. Schindler⁴, Jeffrey L. Dage⁵, Ricardo Allegri⁶, David Aguillon⁷, Tammie Benzinger⁸, Jasmeer Chhatwal⁹, Alisha Daniels⁴, Gregory S. Day¹⁰, Emma Devenney¹¹¹², Nick C. Fox¹³¹⁴, Alison Goate¹⁵, Brian A. Gordon⁸, Nicolas R. Barthélemy¹⁶, Jason Hassenstab⁴, Edward Huey¹⁷, Takeshi Ikeuchi¹⁸, Suman Jayadev¹⁹, Mathias Jucker²⁰²¹, Takanobu Ishiguro²², Jae-Hong Lee²³, Allan I. Levey²⁴, Johannes Levin²⁰²⁵²⁶, John C. Morris²⁷, Richard J. Perrin²⁸, Alan Renton²⁹, Jee Hoon Roh³⁰³¹³², Chengjie Xiong³³, Randall J. Bateman³⁴, Beau M. Ances³⁴, Carlos Cruchaga³⁵³⁶, Celeste M. Karch³⁷, Charlene Supnet-Bell³⁴, Jorge Llibre-Guerra³⁴, Eric McDade³⁴, Dominantly Inherited Alzheimer Network, and Laura Ibanez† ¹²⁴³⁸
¹ Department of Psychiatry, Washington University in Saint Louis School of Medicine, St. Louis, MO 63110, USA
² NeuroGenomics and Informatics Center, Washington University in Saint Louis School of Medicine, St. Louis, MO 63108, USA
³ Department of Neurology, Washington University in Saint Louis School of Medicine, St. Louis, MO 63110, USA
⁴ Department of Neurology, Washington University in Saint Louis School of Medicine, St. Louis, MO 63110, USA
⁵ Department of Neurology, Indiana University, Indianapolis, IN 46202-3082, USA
⁶ Instituto Neurológico Fleni, Buenos Aires, Argentina
⁷ Grupo de Neurociencias de Antioquia (GNA), Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
⁸ Department of Radiology, Washington University in Saint Louis School of Medicine, St. Louis, MO 63110, USA
⁹ Massachusetts General Hospital, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
¹⁰ Department of Neurology, Mayo Clinic in Florida, Jacksonville, FL, USA
¹¹ Neuroscience Research Australia, Sydney NSW 2031, Australia
¹² School of Clinical Medicine, University of New South Wales, Sydney NSW 2052, Australia
¹³ Dementia Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom
¹⁴ UK Dementia Research Institute at UCL, London, United Kingdom
¹⁵ Department of Genetics & Genomic Sciences, Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
¹⁶ Department of Neurology, Washington University School of Medicine, Saint Louis, MO 63110, USA
¹⁷ Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, RI, USA
¹⁸ Brain Research Institute, Niigata University, Niigata 9518585, Japan
¹⁹ Department of Neurology, University of Washington, Seattle, WA, USA
²⁰ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
²¹ Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
²² Brain Research Institute, Niigata University, Niigata, Japan
²³ Department of Neurology, Asan Medical Center, Seoul, Republic of Korea
²⁴ Department of Neurology, Emory University, Atlanta, GA 30329, USA
²⁵ Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
²⁶ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
²⁷ Washington University in St. Louis, Department of Neurology and the Knight Alzheimer Disease Research Center, St. Louis, MO, USA
²⁸ Department of Pathology and Immunology, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
²⁹ Ronald M. Loeb Center for Alzheimer’s Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
³⁰ Department of Neurology, Korea University Anam Hospital, Seoul 02841, Republic of Korea
³¹ Department of Physiology, Korea University College of Medicine, Seoul 02841, Republic of Korea
³² Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea
³³ Department of Statistics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
³⁴ Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
³⁵ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
³⁶ NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA
³⁷ Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA
³⁸ Hope Center for Neurological Disorders, Washington University in Saint Louis School of Medicine, St. Louis, MO 63108, USA
- Authors contributed equally
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