Cerebrospinal fluid NPTX2/p‐tau ratio as a biomarker for cognitive decline in neurodegenerative diseases

Abstract INTRODUCTION Neuronal pentraxin 2 (NPTX2) and its use as a ratio with other synaptic proteins has emerged as a prognostic cerebrospinal fluid (CSF) biomarker across neurodegenerative diseases. METHODS Using a single molecule array (Simoa) method, CSF NPTX2 was measured in 688 individuals from the Sant Pau Initiative on Neurodegeneration, including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration–related disorders (FTLDrs), and cognitively unimpaired (CU) participants. NPTX2/phosphorylated‐tau (p‐tau)181 performance was compared to standalone NPTX2 and p‐tau181. RESULTS The NPTX2/p‐tau ratio enhanced diagnostic performance of standalone NPTX2 and p‐tau, particularly for DLB and FTLDrs (area under the curve [AUC] NPTX2/p‐tau = 0.78–0.79 vs. AUC NPTX2 = 0.63–0.70 and AUC p‐tau = 0.59–0.75), and was more strongly associated with cognition. It also better predicted progression to dementia across the cohort (hazard ratio [HR] = 1.63), especially in AD (HR = 1.84) and DLB (HR = 1.50). DISCUSSION NPTX2/p‐tau may improve prognostic assessments in patients with cognitive impairment, outperforming standalone biomarkers.