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Synapse loss is well-documented in many neurodegenerative diseases, with recently strong associations observed in amyotrophic lateral sclerosis (ALS). Emerging evidence demonstrates thattransactive response DNA binding protein of 43 kDa (TDP-43) pathology, the most prominent hallmark in ALS, is linked to synapse loss, 1 2 as evidenced by the inclusion of a cryptic exon in the Unc 13 Homolog A gene— which plays a key role in synaptic transmission—resulting in synaptic dysfunction.1 A recent study revealed that TDP-43 regulates the expression of neuronal pentraxin 2 (NPTX2) RNA, encoding a synaptic protein involved in synaptic plasticity. Disruption of this regulation leads to NPTX2 accumulation, highlighting another link between TDP-43 dysregulation and synaptic dysfunction.2 Moreover, a recent proteomics study has identified NPTX2 as a cerebrospinal fluid (CSF) biomarker in ALS patients, revealing decreased levels compared with healthy controls (HC).3 Alterations in another synaptic protein, synaptosomal-associated protein of 25 kDa (SNAP-25), have been recently identified in Alzheimer’s disease and other neurodegenerative disorders, reflecting synaptic integrity.4 Here, we measured serum levels of NPTX2 and SNAP25 to assess ALS clinical correlates while benchmarking included synaptic biomarkers against the most well-established blood biomarker in ALS, neurofilament light chain (NfL).