In this study we investigated the cerebrospinal fluid (CSF) levels of neurofilament light (NFL) and heavy chain (NFHp35), total tau (t-tau), and glial fibrillary acidic protein (GFAP) to detect disease specific profiles in sporadic Creutzfeldt Jakob disease (sCJD) patients and Alzheimer's disease (AD) patients. CSF levels of NFL, NFHp35, t-tau, and GFAP of 23 sCJD patients and 55 AD patients were analyzed and compared to non-demented controls. Median NFL, NFHp35, GFAP, and t-tau levels were significantly increased in sCJD patients and AD patients versus controls (p < 0.0001 in all). NFL, NFHp35, and t-tau levels were significantly increased in sCJD patients versus AD patients (p < 0.005), but GFAP concentrations did not differ between sCJD and AD. The results suggest that neuroaxonal damage, reflected by higher CSF levels of NFL, NFHp35, and t-tau, is more pronounced in the pathophysiology of sCJD than in AD. The comparable CSF GFAP concentrations suggest that astroglial damage or astrocytosis is equally pronounced in the pathophysiology of AD and sCJD. Prospective studies are needed to determine whether NFL and NFHp35 may be additional tools in the differential diagnosis of rapidly progressive dementias.