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Relative abundance of 30 pre\u2010defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic <jats:italic>C9orf72<\/jats:italic> HRE carriers and age\u2010matched non\u2010carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Ubiquitin carboxyl\u2010hydrolase isozyme L1 levels were higher in asymptomatic <jats:italic>C9orf72<\/jats:italic> HRE carriers compared with age\u2010matched non\u2010carriers (log<jats:sub>2<\/jats:sub>fold change 0.20, FDR\u2010adjusted <jats:italic>p<\/jats:italic>\u2010value\u2009=\u20090.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl\u2010hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (<jats:italic>p<\/jats:italic>\u2009=\u20090.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (&lt;37) matched by neurofilament level (<jats:italic>p<\/jats:italic>\u2009=\u20090.007).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Elevated cerebrospinal fluid ubiquitin carboxyl\u2010hydrolase isozyme L1 levels in <jats:italic>C9orf72<\/jats:italic> HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the <jats:italic>C9orf72<\/jats:italic> HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. 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