Copyright © 2018 American Academy of Neurology Objective To investigate the clinical utility of 3 CSF biomarkers along the clinical spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods We analyzed 3 CSF biomarkers: the soluble β-fragment of amyloid precursor protein (sAPPβ), YKL-40, and neurofilament light (NfL) in FTD (n = 86), ALS (n = 38), and a group of age-matched cognitively normal controls (n = 49). Participants with FTD with a CSF profile of Alzheimer disease were excluded. We compared cross-sectional biomarker levels between groups, studied their correlation with cognitive and functional scales (global cognitive z score, frontotemporal lobar degeneration Clinical Dementia Rating, revised ALS Functional Rating Scale, and ALS progression rate), survival, and cortical thickness. Results We found increased levels of YKL-40 and decreased levels of sAPPβ in both FTD and ALS groups compared to controls. The lowest sAPPβ levels and sAPPβ/YKL-40 ratio were found in the FTD group. In FTD, sAPPβ and the sAPPβ/YKL-40 ratio correlated with the disease severity. In the whole ALS-FTD spectrum, NfL levels and the NfL:sAPPβ ratio correlated with global cognitive performance (r = −0.41, p < 0.001 and r = −0.44, p < 0.001, respectively). In the ALS group, YKL-40 correlated with disease progression rate (r = 0.51, p = 0.001) and was independently associated with shorter survival. In both FTD and ALS groups, the sAPPβ/YKL-40 ratio showed a positive correlation with cortical thickness in frontotemporal regions. Conclusions sAPPβ, YKL-40, and NfL could represent valuable tools for the staging and prognosis of patients within the ALS-FTD clinical spectrum.