Abnormalities in core AD biomarkers precede inflammatory and glial markers in CSF in Autosomal Dominant Alzheimer’s Disease
BACKGROUND: 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
- Jeff L. Dage
- Emma Devenney (ORCID: https://orcid.org/0000-0001-6140-0452)
- Alisha Daniels (ORCID: https://orcid.org/0009-0001-1464-6465)
- Julie K. Wisch (ORCID: https://orcid.org/0000-0003-3624-2784)
- Gina Jerome
- Matthew Minton
- Ricardo Allegri (ORCID: https://orcid.org/0000-0001-7166-1234)
- Aleksandra Beric (ORCID: https://orcid.org/0000-0002-9351-585X)
- Sam Rose Preminger
- Wenjing Lin
- Jennifer Stauber
- Gregory Day
- Jasmeer Chhatwal
- David Aguillon
- Alison Goate
- Brian A. Gordon
- Tammie L.S. Benzinger
- Nick Fox
- Bryce Baker
- Suzanne E Schindler
Institutions
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Emory University (US)
- Korea University (KR)
- University of Washington (US)
- Washington University in St. Louis (US)
- Brown University (US)
- German Center for Neurodegenerative Diseases (DE)
- Jacksonville College (US)
- Asan Medical Center (KR)
- UNSW Sydney (AU)
- Universidad de Antioquia (CO)
- Massachusetts General Hospital (US)
- Alzheimer’s Disease Neuroimaging Initiative (US)
- Munich Cluster for Systems Neurology (DE)
- Hope Center for Neurological Disorders (US)
- UK Dementia Research Institute (GB)
- Hertie Institute for Clinical Brain Research (DE)
- Mayo Clinic in Florida (US)
- National Hospital for Neurology and Neurosurgery (GB)
- University College London (GB)
- Indiana University – Purdue University Indianapolis (US)
- Niigata University (JP)
- University of Tübingen (DE)
- Ludwig-Maximilians-Universität München (DE)
- Neuroscience Research Australia (AU)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- medRxiv
- Published
- 2026-04-01
- DOI
- https://doi.org/10.64898/2026.03.31.26349851
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
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
- Instituto de Salud Carlos III
- National Institute on Aging