Creutzfeldt-Jakob disease (CJD) is the most common prion disease in humans with an incidence of one case per million inhabitants worldwide. The sporadic form of CJD (sCJD) is spontaneous and accounts for 85% of cases. Its symptoms include rapidly progressive dementia, ataxic gait, personality changes, myoclonus, coma, and eventually death. The challenging diagnosis is currently made by a combination of clinical criteria and supporting tests such as electroencephalography (EEG), magnetic resonance imaging (MRI) findings, and cerebrospinal fluid (CSF) studies. These modalities can be falsely positive or negative in some cases. Therefore, true confirmation usually requires a postmortem brain biopsy. We present a case of a 58-year-old woman who was diagnosed with sporadic form CJD by the novel Real-time Quaking-induced Conversion (RT-QuIC) assay. It is based on an ultrasensitive detection of the pathogenic prion protein in the CSF that directly detects a prion protein rather than a surrogate marker of neurodegeneration such as 14-3-3 or tau protein. The RT-QuIC assay has emerged as the most sensitive and specific CSF study to accurately diagnose sCJD in a living patient, without the need for invasive brain biopsy. The emergence of the nasal brushing RT-QuIC assay may further revolutionize the future of combating prion diseases.