Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration

Saloner, R.; Cornelis, L.; Downer, J.; Dietz, C.; Chan, B.; Hughes, M.; Olzinski, M.; Cobigo, Y.; Lario-Lago, A.; Heuer, H.; Cody, K.; Wood, M.; Cousins, K. A. Q.; Wolk, D.; Lee, E. B.; Irwin, D.; Abdelhak, A.; Boeve, B. F.; Rabinovici, G. D.; La Joie, R.; Grinberg, L. T.; Spina, S.; Paolillo, E. W.; Staffaroni, A.; VandeVrede, L.; Ljubenkov, P. A.; Gorno-Tempini, M. L.; Rosen, H. J.; Yokoyama, J. S.; Kramer, J. H.; Casaletto, K. B.; Miller, B.; Seeley, W. W.; Rojas, J. C.; Boxer, A. L.

doi:10.64898/2026.09.29.755483

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bioRxiv · 10.64898/2026.09.29.755483

Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration

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Abstract

Frontotemporal lobar degeneration (FTLD), predominantly comprised of tau and TDP-43 proteinopathies, is a common cause of early-onset dementia. Biomarkers that reliably classify FTLD subtypes are limited, thereby hindering in-vivo diagnosis and clinical trial stratification. We conducted large-scale, multi-platform cerebrospinal fluid proteomics in 566 individuals, including 274 FTLD-spectrum (48 autopsy-confirmed FTLD-TDP, 90 autopsy-confirmed FTLD-tau), 171 Alzheimers disease, and 95 controls. In neuropathological subtype contrasts, elevated matrix metalloproteinase MMP10 classified Picks disease (PiD) versus other subtypes with near-perfect accuracy across proteomic platforms. We further validated CSF MMP10 as a potential PiD diagnostic biomarker via a targeted immunoassay in an independent, autopsy-confirmed FTLD cohort. Post-synaptic proteins HOMER1 and DLG4 exhibited elevations across FTLD-TDP subtypes (A, B, and C) versus FTLD-tau. Network analysis identified RNA metabolism and pro-inflammatory signatures in FTLD-TDP, and cytoskeletal and heat shock signatures in progressive supranuclear palsy. These findings reveal candidate diagnostic biomarkers and proteomic pathways underlying FTLD clinico-pathological heterogeneity.

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Saloner, R., Cornelis, L., Downer, J., Dietz, C., Chan, B., Hughes, M., Olzinski, M., Cobigo, Y., Lario-Lago, A., Heuer, H., Cody, K., Wood, M., Cousins, K. A. Q., Wolk, D., Lee, E. B., Irwin, D., Abdelhak, A., Boeve, B. F., Rabinovici, G. D., La Joie, R., Grinberg, L. T., Spina, S., Paolillo, E. W., Staffaroni, A., VandeVrede, L., Ljubenkov, P. A., Gorno-Tempini, M. L., Rosen, H. J., Yokoyama, J. S., Kramer, J. H., Casaletto, K. B., Miller, B., Seeley, W. W., Rojas, J. C., Boxer, A. L.. 2026-10-08. Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration. https://doi.org/10.64898/2026.09.29.755483

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