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

Accurate prediction of which patients with mild cognitive impairment (MCI) will progress to dementia remains a major challenge. Current biomarkers detect amyloid pathology with high accuracy but offer limited prognostic value for disease progression. We conducted a prospective analysis in the multicentre BALTAZAR cohort, all diagnosed with MCI at baseline and followed for 3 years. Paired cerebrospinal fluid (CSF) and plasma samples were analysed with the NULISA ultrasensitive multiplex platform quantifying more than 120 central nervous system biomarkers. Prognostic performance was assessed using area under the curve (AUC) and hazard ratios (HRs), both for individual markers and for elastic-net-derived biomarker combinations validated by bootstrap and survival analyses. During the 3-year follow-up, 36% of participants converted to dementia. 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, NfL) and synaptic dysfunction (NPTX2 encoding the Neuronal Pentraxin 2) predicted conversion with higher accuracy, 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 (p-tau181 or p-tau217 with YWHAG encoding for 14-3-3 protein gamma, a member of the 14-3-3 protein family) provided only modest improvement, likely reflecting the absence of robust synaptic markers in blood. Prognostic assessment of MCI progression to dementia is best achieved through CSF biomarker combinations reflecting neurodegeneration and synaptic dysfunction, complemented by inflammatory markers. These findings emphasize the clinical and pathophysiological relevance of downstream processes beyond amyloid and tau, and support the implementation of multimarker panels for prognosis and therapeutic monitoring.