A number of unexpected pathophysiological connections linking different neurodegenerative diseases have emerged over the past decade. An example is provided by prion and Alzheimer's diseases. Despite being distinct pathologies, these disorders share several neurotoxic mechanisms, including accumulation of misfolded protein isoforms, stress of the protein synthesis machinery, and activation of a neurotoxic signaling mediated by the cellular prion protein. Here, in addition to reviewing these mechanisms, we will discuss the potential therapeutic interventions for prion and Alzheimer's diseases that are arising from the comprehension of their common neurodegenerative pathways.