Abstract Brain atrophy has been reported in the early stages of Parkinson’s disease, but there have been few longitudinal studies. How intrinsic properties of the brain, such as anatomical connectivity, local cell-type distribution and gene expression combine to determine the pattern of disease progression also remains unknown. One hypothesis proposes that the disease stems from prion-like propagation of misfolded alpha-synuclein via the connectome that might cause varying degrees of tissue damage based on local properties. Here, we used MRI data from the Parkinson Progression Markers Initiative to map the progression of brain atrophy over 1, 2 and 4 years compared with baseline. We derived atrophy maps for four time points using deformation-based morphometry applied to T1-weighted MRI from 120 de novo Parkinson’s disease patients, 74 of whom had imaging at all four time points (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). In order to determine factors that may influence neurodegeneration, we related atrophy progression to brain structural and functional connectivity, cell-type expression and gene ontology enrichment analyses. After regressing out the expected age and sex effects associated with normal ageing, we found that atrophy significantly progressed over 2 and 4 years in the caudate, nucleus accumbens, hippocampus and posterior cortical regions. This progression was shaped by both structural and functional brain connectivity. Also, the progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses and was inversely related to the prevalence of oligodendrocytes and endothelial cells. In sum, we demonstrate that the progression of atrophy in Parkinson’s disease is in line with the prion-like propagation hypothesis of alpha-synuclein and provide evidence that synapses may be especially vulnerable to synucleinopathy. In addition to identifying vulnerable brain regions, this study reveals different factors that may be implicated in the neurotoxic mechanisms leading to progression in Parkinson’s disease. All brain maps generated here are available on request.