In this cross-sectional study that included 576 participants, serum L1CAM-positive extracellular vesicle (L1EV)-associated α-synuclein differentiated at-risk participants with more than 80% probability of having prodromal Parkinson disease from controls and correctly identified 80% of those who phenoconverted to Parkinson disease and related dementia. The gene discussed is L1CAM; the disease is dementia.