Fig. 1.

Overview of approach. In this study, anterior cingulate cortex was sampled from a cohort of 28 individuals divided equally between four groups: non-neurological controls; Parkinson’s disease without cognitive impairment (PD); Parkinson’s disease with dementia (PDD); and dementia with Lewy bodies (DLB) (Supplementary Fig. 1, Supplementary Table 1). For each individual, a frozen tissue block derived from the anterior cingulate was sectioned (sectioned area indicated with green shaded box), with adjacent sections used for single-nucleus or bulk-tissue RNA-sequencing (Supplementary Fig. 2, Supplementary Fig. 3, Supplementary Table 1). Following data pre-processing, single-nucleus RNA-sequencing data was used to generate cell-type-specific differential gene expression profiles and to deconvolute bulk-tissue RNA-sequencing data. Bulk-tissue RNA-sequencing was used in differential gene expression and splicing analyses, with cell-type proportions included as model covariates in both analyses. Results from single-nucleus RNA-sequencing and bulk-tissue RNA-sequencing were used in downstream gene set enrichment analyses to identify disease-relevant pathways. Furthermore, common risk variants for Alzheimer’s disease (AD), PD risk and PD age of onset (PD AOO) were mapped to cell-type-specific expression profiles and cell-type-specific differential expression. The image of the human brain displays a coronal section cut at the level of nucleus accumbens. RNA-seq RNA-sequencing, UMI unique molecular identifier