Prions are lethal infectious agents thought to consist of multi-chain forms (PrP^Sc) of misfolded cellular prion protein (PrP^C). Prion propagation proceeds in two distinct mechanistic phases: an exponential phase 1, which rapidly reaches a fixed level of infectivity irrespective of PrP^C expression level, and a plateau (phase 2), which continues until clinical onset with duration inversely proportional to PrP^C expression level. We hypothesized that neurotoxicity relates to distinct neurotoxic species produced following a pathway switch when prion levels saturate. Here we show a linear increase of proteinase K-sensitive PrP isoforms distinct from classical PrP^Sc at a rate proportional to PrP^C concentration, commencing at the phase transition and rising until clinical onset. The unaltered level of total PrP during phase 1, when prion infectivity increases a million-fold, indicates that prions comprise a small minority of total PrP. This is consistent with PrP^C concentration not being rate limiting to exponential prion propagation and neurotoxicity relating to critical concentrations of alternate PrP isoforms whose production is PrP^C concentration dependent.