I. Kowal, S. W. Scholz, J. Epstein, B. J. Traynor, L. E. Danielian, Y. Hao, J. Crook, Z. Li, K. Porter, B. Sellers, T. J. Langowski, M. N. Denkinger, N. J. Ashton, K. Van Keuron-Jensen, M. R. Cookson, J. Y. Kwan, Y. A. A. Qi, A. Snyder
INTRODUCTION: Understanding concordance across biofluids and platforms is critical for understanding neurodegenerative biomarkers results and translating them into clinical use; yet systematic comparisons remain limited. To address this gap, we performed large-scale proteomic profiling of patient-paired plasma and CSF to characterize cross-modal relationships. METHODS: We profiled paired plasma and CSF from 67 individuals using SomaScan 11K and NULISAseq CNS panels. Disease severity was assessed with the CDR+NACC FTLD-M Global Score. RESULTS: We identified 269 SomaScan and 18 NULISA proteins with significant cross-biofluid correlation. Cross-platform concordance within biofluids was strong. NEFL, NPTX2, TREM2, and CHIT1 demonstrated consistent cross-platform agreement. Associations with disease severity were compartment-specific, with decreased NPTX2 in CSF, increased NEFL and GFAP in plasma, and decreased TREM2 across biofluids. DISCUSSION: Cross-platform consistency supports biomarker robustness, while limited cross-biofluid concordance highlights compartmental biology. Given additional clinical correlations despite varying underlying pathology, these findings may point to shared neurodegenerative disorder pathways.