In summary, we report a new, exceptionally large PARK4 pedigree, provide proof of principle that the risk for a future manifestation of PD is reflected in the global transcriptome of blood, identify diverse pathways and, in particular, the levels of SPP1, GZMH, PLTP and CPLX1 as biomarkers of pathogenesis, show subtle CPLX1 downregulations to distinguish prodromal PD cohorts (presymptomatic PARK4 heterozygotes and RBD individuals) from controls, and suggest that complexin 1 loss of function acts as a PD risk factor. The gene discussed is SNCA; the disease is Parkinson disease.