Emerging evidence implicating glymphatic dysfunction contributes to the pathogenesis of frontotemporal dementia (FTD). However, the pathway correlated to glymphatic function in FTD remains poorly understood. We aimed to explore potential underlying metabolic pathways associated with glymphatic dysfunction in FTD.We enrolled 37 behavior FTD (bvFTD) patients and 40 healthy controls. Glymphatic activity was assessed using diffusion tensor imaging data. Plasma metabolomic profiling was performed to identify glymphatic-associated metabolites, followed by pathway enrichment analysis. Additionally, the plasma biomarker was tested in a subset of 25 patients to validate the metabolite findings.Patients with bvFTD exhibited significantly altered metabolite profiles compared to controls. The glymphatic-associated metabolites were predominantly enriched in the synaptic vesicle cycle pathway (FDR p < 0.05). Furthermore, plasma neuropentraxin-2 (NPTX2) levels positively correlated with anterior glymphatic indices (r = 0.46, p = 0.027).Our findings demonstrate the association between the glymphatic system and synaptic function in bvFTD.Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.