Beyond amyloid and tau: synaptic and neurodegenerative biomarkers shape MCI progression

Background Accurate prediction of which patients with mild cognitive impairment (MCI) will progress to Alzheimer 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.