Figure 2.

Alpha-synuclein propagation and Parkinson disease dementia. In the early stage of Parkinson disease, the initial alpha-synuclein (αS) pathology originates in the enteric nervous system and spreads to the CNS via the bilateral vagal innervation (body-first subtype) or originates in the unilateral amygdala and spreads to predominantly the ipsilateral hemisphere (brain-first subtype). When the global burden of αS pathology increases with time, indicated by the blue arrow to the right side and the right triangle under the brain figures, patients with Parkinson disease may develop dementia. Genetic mutation, aging, and the exposome—an integrated function of exposure—contribute to an increased burden of αS and consequent fibrillation. αS can spread from cell to cell and interact with both biological proteins and pathogenic proteins such as Aβ and tau. The vicious cycle between αS propagation and dysregulation of protein–protein interaction further enhances neurodegeneration. Aβ, Amyloid-β; αS, alpha-synuclein; CNS, central nervous system. Created with BioRender.com (accessed on 12 October 2021).