Significance Single-cell transcriptomics has revealed specific glial activation states associated with the pathogenesis of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease (AD and PD). What is still needed are clinically relevant biomarkers for deciphering such glial states in AD and PD patients. To this end, we applied proteome analysis in cerebrospinal fluid (CSF) of mouse models of AD and PD pathology. This allowed us to identify a panel of glial CSF proteins that largely match the transcriptomic changes. The identified proteins can also be quantified in human CSF and show changes in AD patients, supporting their relevance as biomarker candidates to stage glial activation in patients with neurodegenerative diseases.