Olfactory swab (OS or nasal brushing) is a non-invasive procedure that can be easily performed by non-ENT with a diagnostic accuracy comparable to CSF. First, in 10-15% of patients, lumbar puncture is not practicable, for reasons including behavioral changes occurring in patients with prion disorders, spine arthrosis, or anticoagulant intake. Second, OS is a reliable and sensitive procedure that allows a diagnostic accuracy of prion disorder of nearly 100% when combined with CSF. This is relevant for prompt diagnosis communication and monitoring disease-modifying therapies’ efficacy by serial OM collection. This approach would also be applied in carriers of PRNP mutations in a presymptomatic stage to demonstrate potential RT-QuIC positivity close to the development of clinical symptoms. Finally, this large-scale and multicentric study will determine the reliability of the OS approach performed anywhere, to simplify the CJD diagnosis process.