Cerebrospinal fluid YWHAG:NPTX2 ratio predicts clinical severity and future phenoconversion in frontotemporal lobar degeneration
Abstract
Frontotemporal lobar degeneration (FTLD) is a common cause of early-onset dementias marked by progressive declines in behavior, cognition, and/or movement. FTLD neuropathologies, including TDP-43 proteinopathies and primary tauopathies, do not have reliable fluid biomarkers for in-vivo diagnosis nor biomarkers that directly correspond to FTLD clinical features. Fluid biomarkers that forecast and track FTLD clinical progression, irrespective of pathology or clinical syndrome, are urgently needed to improve clinical trial designs. We previously identified the ratio between two cerebrospinal fluid (CSF) synaptic proteins, YWHAG and NPTX2, as a prognostic biomarker of cognitive decline in Alzheimers disease (AD), independent of core AD pathologies, amyloid and tau. Here, we evaluate its utility in sporadic and familial FTLD compared to other neurodegenerative diseases. Using CSF assays from four independent cohorts (UCSF-MAC, ALLFTD, GENFI, PDBP), we find CSF YWHAG:NPTX2 is substantially elevated across all sporadic and familial FTLD syndromes, AD, and dementia with Lewy bodies. CSF YWHAG:NPTX2 robustly correlates with clinical severity across sporadic and familial FTLD (C9orf72, GRN, or MAPT mutations), independent of current gold-standard neurodegeneration biomarker neurofilament light (NfL). In presymptomatic familial FTLD, CSF YWHAG:NPTX2 is estimated to rise roughly a decade before symptom onset and improves prediction of imminent symptomatic conversion by 1.7-fold compared to plasma NfL alone, more than halving the estimated sample size required for an FTLD prevention clinical trial. These findings underscore CSF YWHAG:NPTX2 as a cross-dementia synaptic biomarker of cognitive decline and a promising biomarker for disease staging and prognosis across the clinico-pathological continuum of FTLD.
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BibTeX
@misc{oh2026cerebrospinal,
title = {{Cerebrospinal fluid YWHAG:NPTX2 ratio predicts clinical severity and future phenoconversion in frontotemporal lobar degeneration}},
author = {H. S.-H. Oh and J. D. Downer and C. D. Dietz and C. Yballa and E. Marcora and A. Lario-Lago and H. W. Heuer and L. K. Forsberg and J. Hsiao-Nakamoto and C.-L. Chiu and P. Auger and C. Powers and G. Di Paolo and F. Huang and B. Appleby and S. Barmada and E. Bayram and A. Bozoki and D. Clark and R. R. Darby and B. Dickerson and K. Domoto-Reilly and K. Faber and A. Fagan and T. Foroud and D. R. Galasko and D. Geschwind and N. Ghoshal and N. Graff-Radford and I. M. Grant and C. M. Hales and L. S. Honig and G.-Y. Hsiung and E. D. Huey and D. Irwin and D. Knopman and J. Kornak and J. Kwan and G. C. Leger and I. Litvan and I. R. Mackenzie and M. F. Mendez and C. Onyike and B. Pascual},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.22.746470},
url = {https://www.biorxiv.org/content/10.64898/2026.08.22.746470v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cerebrospinal fluid YWHAG:NPTX2 ratio predicts clinical severity and future phenoconversion in frontotemporal lobar degeneration
AU - H. S.-H. Oh
AU - J. D. Downer
AU - C. D. Dietz
AU - C. Yballa
AU - E. Marcora
AU - A. Lario-Lago
AU - H. W. Heuer
AU - L. K. Forsberg
AU - J. Hsiao-Nakamoto
AU - C.-L. Chiu
AU - P. Auger
AU - C. Powers
AU - G. Di Paolo
AU - F. Huang
AU - B. Appleby
AU - S. Barmada
AU - E. Bayram
AU - A. Bozoki
AU - D. Clark
AU - R. R. Darby
AU - B. Dickerson
AU - K. Domoto-Reilly
AU - K. Faber
AU - A. Fagan
AU - T. Foroud
AU - D. R. Galasko
AU - D. Geschwind
AU - N. Ghoshal
AU - N. Graff-Radford
AU - I. M. Grant
AU - C. M. Hales
AU - L. S. Honig
AU - G.-Y. Hsiung
AU - E. D. Huey
AU - D. Irwin
AU - D. Knopman
AU - J. Kornak
AU - J. Kwan
AU - G. C. Leger
AU - I. Litvan
AU - I. R. Mackenzie
AU - M. F. Mendez
AU - C. Onyike
AU - B. Pascual
PY - 2026
DA - 2026/08/22
PB - bioRxiv
DO - 10.64898/2026.08.22.746470
UR - https://www.biorxiv.org/content/10.64898/2026.08.22.746470v1
AB - Frontotemporal lobar degeneration (FTLD) is a common cause of early-onset dementias marked by progressive declines in behavior, cognition, and/or movement. FTLD neuropathologies, including TDP-43 proteinopathies and primary tauopathies, do not have reliable fluid biomarkers for in-vivo diagnosis nor biomarkers that directly correspond to FTLD clinical features. Fluid biomarkers that forecast and track FTLD clinical progression, irrespective of pathology or clinical syndrome, are urgently needed to improve clinical trial designs. We previously identified the ratio between two cerebrospinal fluid (CSF) synaptic proteins, YWHAG and NPTX2, as a prognostic biomarker of cognitive decline in Alzheimers disease (AD), independent of core AD pathologies, amyloid and tau. Here, we evaluate its utility in sporadic and familial FTLD compared to other neurodegenerative diseases. Using CSF assays from four independent cohorts (UCSF-MAC, ALLFTD, GENFI, PDBP), we find CSF YWHAG:NPTX2 is substantially elevated across all sporadic and familial FTLD syndromes, AD, and dementia with Lewy bodies. CSF YWHAG:NPTX2 robustly correlates with clinical severity across sporadic and familial FTLD (C9orf72, GRN, or MAPT mutations), independent of current gold-standard neurodegeneration biomarker neurofilament light (NfL). In presymptomatic familial FTLD, CSF YWHAG:NPTX2 is estimated to rise roughly a decade before symptom onset and improves prediction of imminent symptomatic conversion by 1.7-fold compared to plasma NfL alone, more than halving the estimated sample size required for an FTLD prevention clinical trial. These findings underscore CSF YWHAG:NPTX2 as a cross-dementia synaptic biomarker of cognitive decline and a promising biomarker for disease staging and prognosis across the clinico-pathological continuum of FTLD.
ER -