Plasma total and nervous system derived exosomal (NDE) α-synuclein have been determined as potential biomarkers of Parkinson's disease (PD). To explore the utility of plasma α-synuclein in the prodromal phase of PD, plasma total and NDE α-synuclein were evaluated in baseline and 2-year follow-up samples from 256 individuals recruited as part of the Parkinson's Associated Risk Syndrome (PARS) study. The results demonstrated that baseline and longitudinal increases in total α-synuclein predicted progression of cognitive decline in hyposmic individuals with dopamine transporter (DAT) binding reduction. On the other hand, a longitudinal decrease in NDE α-synuclein predicted worsening cognitive scores in hyposmic individuals with DAT binding reduction. Finally, in individuals with faster DAT progression, decreasing NDE/total α-synuclein ratio was associated with a larger reduction in DAT from baseline to follow-up. These results suggest that, though underlying mechanisms remain to be defined, alterations in plasma total and NDE α-synuclein concentrations are likely associated with PD progression, especially in the aspect of cognitive impairment, at early stages of the disease.