The soluble cellular prion protein (PrP(C)) is best known for its association with prion disease (PrD) through its conversion to a pathogenic insoluble isoform (PrP(Sc)). However, its deleterious effects independent of PrP(Sc) have recently been observed not only in PrD but also in Alzheimer disease (AD), two diseases which mainly affect cognition. At the same time, PrP(C) itself seems to have broad physiologic functions including involvement in cognitive processes. The PrP(C) that is believed to be soluble and monomeric has so far been the only PrP conformer observed in the uninfected brain. In 2006, we identified an insoluble PrP(C) conformer (termed iPrP(C) ) in uninfected human and animal brains. Remarkably, the PrP(Sc) -like iPrPC shares the immunoreactivity behavior and fragmentation with a newly-identified PrP(Sc) species in a novel human PrD termed variably protease-sensitive prionopathy. Moreover, iPrP(C) has been observed as the major PrP species that interacts with amyloid β (Aβ) in AD. This article highlights evidence of PrP involvement in two putatively beneficial and deleterious PrP-implicated pathways in cognition, and hypothesizes first, that beneficial and deleterious effects of PrP(C) are attributable to the chameleon-like conformation of the protein and second, that the iPrP(C) conformer is associated with PrD and AD.