Abnormalities in core AD biomarkers precede inflammatory and glial markers in CSF in Autosomal Dominant Alzheimer’s Disease
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Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Abnormalities in core AD biomarkers precede inflammatory and glial markers in CSF in Autosomal Dominant Alzheimer’s Disease
- Date Crossref
- 01/04/2026
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
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Washington University in St. Louis pays non établi dans la noticeUniversité ou école supérieure
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Indiana University – Purdue University Indianapolis Department of Neurology pays non établi dans la noticeUniversité ou école supérieure
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Universidad de Antioquia pays non établi dans la noticeUniversité ou école supérieure
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Washington University in St. Louis, Department of Neurology — Indiana University – Purdue University Indianapolis et Universidad de Antioquia, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.