Previous therapies tested in animal models of prion disease have been highly effective prophylactically but have shown little or no efficacy when administered at the symptomatic stage of disease, suggesting that a preventive approach may be essential in humans.

We assembled age of onset or death data from N=1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age of onset. We used formulae and simulations to estimate statistical power for clinical trials.

Genetic prion disease age of onset varies over several decades for the most common mutations and is not explained by sex, parent’s age of onset, or PRNP codon 129 genotype. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.