Amyloid precursor protein (APP) accumulation in axonal ovoids is a sensitive marker for acute axonal injury in multiple sclerosis (MS) lesions. This study measured levels of α-cleaved soluble APP (α sAPP) and β-amyloid 42 (Aβ42) in the cerebrospinal fluid (CSF) of 42 MS, 10 neuromyelitis optica and 25 clinically isolated syndrome patients and 21 healthy controls, and analysed the correlation between αsAPP and Aβ42 levels and relevant clinical parameters. The CSF concentrations of αsAPP and Aβ42 in patients and controls were not significantly different. There was a significant inverse correlation in patientsbetween CSF αsAPP concentration and the Expanded Disability Status Scale (EDSS), but no significant correlation between CSF Aβ42 concentration and EDSS. The concentration of αsAPP in the CSF of statin-treated patients was significantly higher than in those not treated with statins, suggesting that statins may have a neuroprotective effect. In conclusion, αsAPP was present at similar levels in the CSF of patients with neuromyelitis optica, MS and clinically isolated syndrome and healthy controls, and an inverse correlation existed between CSF αsAPP concentration and neurological disability.