- October 7, 2025
- Sylvain Lehmann, et al., Université de Montpellier
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Mild Cognitive Impairment (MCI)
Sample Type:
CSF, Plasma
Abstract
Background Accurate prediction of which patients with mild cognitive impairment (MCI) will progress to Alzheimer’s disease (AD) remains a major unmet clinical need. Current biomarkers detect amyloid pathology with high accuracy but offer limited prognostic value for disease progression.
Methods We conducted a prospective analysis in the multicentre BALTAZAR cohort (NCT01315639), all diagnosed with MCI at baseline and followed clinically for 3 years. Paired cerebrospinal fluid (CSF) and plasma samples were collected on the same day and analysed with the NULISA ultrasensitive multimarker platform quantifying 120 central nervous system biomarkers. Prognostic performance for conversion to AD dementia was assessed using area under the receiver operating characteristic curve (AUC) and hazard ratios (HRs), both for individual markers and for elastic-net–derived biomarker combinations validated by bootstrap and survival analyses.
Findings During the 3-year follow-up, 63% of participants converted to AD. Plasma p-tau biomarkers showed strong accuracy for detecting amyloid positivity (AUC > 0·90) but limited prognostic value for conversion (AUC < 0·75). In CSF, markers of neurodegeneration (tau, p-tau181, NfL) and synaptic dysfunction (NPTX2) predicted conversion with higher accuracy, matching or exceeding p-tau217 performance. The best-performing CSF combination (IL-16, tau, NPTX2) achieved an AUC of 0·86 (95% CI 0·80–0·91) and an HR of 39·8 (95% CI 9·6–165·2). Plasma combinations (e.g., p-tau181 or p-tau217 with YWHAG) provided only modest improvement, likely reflecting the absence of robust synaptic markers in blood.
Interpretation Prognostic assessment of MCI progression to AD is best achieved through CSF biomarker combinations reflecting neurodegeneration and synaptic dysfunction, complemented by inflammatory markers. These findings emphasise the clinical and pathophysiological relevance of downstream processes beyond amyloid and tau, and support the implementation of multimarker panels for prognosis and therapeutic monitoring.
Authors & Affiliations
Constance Delaby14, Susanna Schraen-Maschke2, Claire Paquet6, Frédéric Blanc5, Jean-Sébastien Vidal3, Christophe Hirtz1, Said Assous10, Bernadette Allinquant7, Stéphanie Bombois8, Audrey Gabelle9, Olivier Hanon3*, Sylvain Lehmann1* and the Balazar study group
1. LBPC-PPC, Université de Montpellier, INM INSERM, IRMB CHU de Montpellier, Montpellier, France
2. Univ. Lille, Inserm, CHU Lille, UMR-S-U1172, LiCEND, Lille Neuroscience & Cognition, LabEx DISTALZ, F-59000, Lille, France
3. Université Paris Cité, UMR-S 1144, APHP, Hospital Broca, Memory Resource and Research Centre of de Paris-Broca-Ile de France, F-75013 Paris, France
4. Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau – Biomedical Research Institute Sant Pau – Universitat Autònoma de Barcelona, Barcelona, Spain
5. Université de Strasbourg, CHRU de Strasbourg, Memory Resource and Research Centre of Strasbourg/Colmar, French National Centre for Scientific Research (CNRS), ICube Laboratory and Fédération de Médecine Translationnelle de Strasbourg (FMTS), Team Imagerie Multimodale Intégrative en Santé (IMIS)/Neurocrypto, F-67000 Strasbourg, France
6. Université Paris Cité, GHU APHP Nord Lariboisière Fernand Widal, Centre de Neurologie Cognitive, F-75010 Paris, France
7. UMR-S1266, Université Paris Cité, Institute of Psychiatry and Neuroscience, Inserm, Paris, France
8. Assistance Publique-Hôpitaux de Paris (AP-HP), Département de Neurologie, Centre des Maladies Cognitives et Comportementales, GH Pitié-Salpêtrière, Paris, France
9. Université de Montpellier, Memory Research and Resources center, department of Neurology, Inserm INM NeuroPEPs team, F-34000 Montpellier, France
10. Institute for Regenerative Medicine and Biotherapy (IRMB), University of Montpellier, INSERM, CHU Montpellier, 34295 Montpellier, France