In the present study, we analyzed the transcriptome of brain regions involved in Braak LB stages18 of non-neurological adult donors from the AHBA to reveal molecular factors underlying selective vulnerability to LB pathology during PD progression. We validated our findings in two independent non-neurological datasets (the Genotype-Tissue Expression project (GTEx)19 and UK Brain Expression Consortium (UKBEC)20). Further, we showed that Braak stage-related genes (BRGs) are indeed progressively disrupted in patients with incidental Lewy body disease (iLBD; assumed to represent the pre-clinical stage of PD11,21) and PD. The observed transcriptomic signatures of vulnerable brain regions pointed towards the dopamine biosynthetic process and oxygen transport that were highly expressed in brain regions related to the preclinical stages of PD. Together, our analyses provide important insights that enable a better understanding of the biological mechanisms underlying disease progression.
