Abnormalities in core AD biomarkers precede inflammatory and glial markers in CSF in Autosomal Dominant Alzheimer’s Disease
Year: 2026
Type: preprint
Abstract: 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. FUNDING National Institute on Aging, Alzheimer’s Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea, Spanish Institute of Health Carlos III.
Source: medRxiv
Authors: Wenjing Lin, Aleksandra Beric, Julie K. Wisch, Bryce Baker, Gina Jerome, Matthew Minton, Sam Preminger, Jennifer Stauber, Suzanne E. Schindler, Jeffrey L. Dage, Ricardo Allegri, David Aguillon, Tammie Benzinger, Jasmeer Chhatwal, Alisha Daniels, Gregory S. Day, Emma Devenney, Nick C. Fox, Alison Goate, Brian A. Gordon, Nicolas R. Barthélemy, Jason Hassenstab, Edward Huey, Takeshi Ikeuchi, Suman Jayadev, Mathias Jucker, Takanobu Ishiguro, Jae-Hong Lee, Allan I. Levey, Johannes Levin, John C Morris, Richard J. Perrin, Alan Renton, Jee Hoon Roh, Chengjie Xiong, Randall J. Bateman, Beau M. Ances, Carlos Cruchaga, Celeste M. Karch, Charlene Supnet-Bell, Jorge Llibre-Guerra, Eric McDade, Dominantly Inherited Alzheimer Network, Laura Ibanez
Institutions: Washington University in St. Louis, Indiana University Indianapolis, Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Universidad de Antioquia, Brigham and Women's Hospital, Harvard University, Massachusetts General Hospital, Mayo Clinic in Florida, UNSW Sydney, Neuroscience Research Australia, UK Dementia Research Institute, UCL Queen Square Institute of Neurology, University College London, Icahn School of Medicine at Mount Sinai, Brown University, Niigata University, University of Washington, German Center for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Asan Medical Center, Emory University, Munich Cluster for Systems Neurology, Ludwig-Maximilians-Universität München, Korea University, Korea University Anam Hospital, Hope Center for Neurological Disorders
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Alzheimer's Association, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ministry of Science and ICT, South Korea, Fleni, National Institutes of Health, Instituto de Salud Carlos III, National Institute on Aging
OpenAlex ID: W7147148295
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