In PD, the progressive accumulation of LB pathology across the brain follows a characteristic pattern, which starts in the brainstem and subsequently evolves to more rostral sites of the brain (Braak ascending scheme)1. Using transcriptomic data of non-neurological brains, we identified genes (e.g., SNCA, SCARB2, and ZNF184) and modules of co-expressed genes for which the expression decreased or increased across brain regions defined by the Braak ascending scheme. Interestingly, these patterns were disrupted in brains of PD patients across regions that are preclinically involved in the pathophysiology of PD. One gene co-expression module that showed higher expression in preclinically involved regions was related to dopamine synthesis, locomotory behavior, and microglial and neuronal activity. Another module was related to blood-oxygen transport, the immune system, and may involve endothelial cells. Our results highlight the complex genetic architecture of PD in which the combined effects of genetic variants and co-expressed genes may underlie the selective regional vulnerability of the brain.
