Neurogenetic traits outline vulnerability to cortical disruption in Parkinson’s disease

•In this study we characterized in vivo large-scale propagation pathways of α-synuclein pathology and identified different patterns of functional connectivity disruptions in PD patients at different stages of the disease.•Our results identified key genetic signatures of large-scale PD pathology, highlighting their contribution to focal neuronal vulnerability to disease progression.•Our results pave the way toward better accounting for the brain networks complexity and mechanisms underlying distinct spatial vulnerability to PD pathology, thus informing early diagnosis and future novel therapeutic strategies. The genetic traits that underlie vulnerability to neuronal damage across specific brain circuits in Parkinson’s disease (PD) remain to be elucidated. In this study, we characterized the brain topological intersection between propagating connectivity networks in controls and PD participants and gene expression patterns across the human cortex – such as the SNCA gene. We observed that brain connectivity originated from PD-related pathology epicenters in the brainstem recapitulated the anatomical distribution of alpha-synuclein histopathology in postmortem data. We also discovered that the gene set most related to cortical propagation patterns of PD-related pathology was primarily involved in microtubule cellular components. Thus, this study sheds light on new avenues for enhancing detection of PD neuronal vulnerability via an evaluation of in vivo connectivity trajectories across the human brain and successful integration of neuroimaging-genetic strategies.