Reelin is an essential glycoprotein for correct cytoarchitectonic organization during CNS development. Its function in the adult brain is far less well understood, but altered brain and blood reelin levels have been reported in some psychiatric disorders, and the possibility has been considered of an involvement of the reelin signaling pathway in neurodegeneration. Here we report, for the first time, the presence of detectable levels of reelin in rat and human cerebrospinal fluid (CSF) and show evidence for the involvement of a 180-kDa reelin fragment in two neurodegenerative disorders. This fragment was analyzed by Western blotting in CSF samples from 13 healthy control individuals and 14 frontotemporal dementia (FTD) and 20 Alzheimer's disease (AD) patients. Increased CSF 180-kDa reelin was found in FTD (161.7 ± 6.7 arbitrary units; a.u.) and AD (151.4 ± 3.8 a.u.) compared with control individuals (141.4 ± 1.2 a.u., P < 0.05). Our results strongly suggest the involvement of reelin signaling in neurodegenerative pathologies. © 2003 Wiley-Liss, Inc.