Soluble PrP in CSF is reduced in symptomatic prion disease patients, presumably as a result of a disease sink process,12 and yet pharmacologic lowering of CSF PrP may be important as a drug activity biomarker for trials of PrP-lowering drugs, and has been proposed as a surrogate endpoint in prevention trials.12 Our data suggest CSF PrP does not decline prior to symptom onset, even in the presence of RT-QuIC positivity, suggesting its use in asymptomatic individuals will not be confounded. This evidence concerns the gene PRNP and prion disease.