CSF PrP-amyloid seeding predicts clinical onset in inherited prion disease

Silent proteopathic seed propagation is hypothesised to precede neurodegenerative disease, but direct evidence that it signals near-term clinical conversion in humans is lacking. In prion disease, a prototypic disorder of proteopathic seeding, cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) offers a direct measure of prion protein amyloid seeding activity. We analysed longitudinal CSF RT-QuIC data from 94 PRNP E200K mutation carriers across international natural history cohorts to determine whether seeding status predicts clinical conversion. Eleven carriers developed inherited prion disease; all showed at least one positive RT-QuIC result before onset. First positivity appeared a median of 2.0 years prior to symptoms (IQR 1.3-3.3; range 0.2-4.8). Landmark analyses showed RT-QuIC positivity identified a markedly increased short-term conversion risk, whereas persistently asymptomatic carriers remained negative throughout follow-up. These findings establish CSF RT-QuIC positivity as a biomarker-defined state of incipient conversion in E200K carriers, informing risk stratification and preventive trial design.