Background Lewy Body Dementias (LBD) include Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD). DLB is the second most common neurodegenerative dementia, and it is associated with increased mortality, earlier nursing home admissions, higher risk of falls, poorer quality-of-life, more health resource utilisation, higher costs, and more caregivers’ burden than Alzheimer's disease. There are no disease-modifying treatments for LBD, and reliable cost-effective biomarkers that can aid early diagnosis of LBD remain elusive. Identifying Differentially Expressed Genes (DEG) in LBD brains can reveal underlying functionally disrupted molecular pathways, and it may lead to novel biomarkers and potential RNA drugs for LBD. However, relevant studies investigating transcriptomics of LBD remain sparse. Methods We studied anterior cingulate and dorsolateral prefrontal cortices of post-mortem pathology-verified brains from the following three groups, (i) DLB (n=7), (ii) PDD (n=7), and (iii) non-demented older people (n=6). Total RNA was extracted, and their quality was assessed by Agilent 2100 Bioanalyzer (N=40). Next-generation RNA-sequencing (RNA-seq) (75 bp; paired-end; minimum 30 million clean reads/ sample) was completed using Illumina HiSeq-4000. After appropriate quality control, reads were aligned to the human genome by HISAT2. Aligned reads were counted by featureCounts, and DEG were identified by edgeR 3.18.1 with Benjamini-Hochberg false discovery correction (5%). Functional analyses of identified DEGs were performed using Ingenuity Pathway Analysis. Subgroup analyses were performed between LBD with and without pathogenic GBA (Glucosidase, Beta Acid) mutations. Results We have identified specific significantly upregulated and downregulated DEGs in LBD, while comparing with non-demented older people. Downregulated DEGs in LBD include Oxytocin Receptor (OXTR), Myeloperoxidase (MPO), Selectin E (SELE), Cathepsin G (CTSG), and Somatostatin (SST), and upregulated DEGs in LBD include X-Inactive Specific Transcript (XIST), Polypeptide N-acetyl galactosaminyl transferase 6 (GALNT6), and mitochondrial Proline dehydrogenase (PRODH). DEGs in LBD are significantly enriched for prion diseases, cytokine-cytokine receptor interaction, phagosome, and glycerophospholipid metabolism pathways. We have also identified the DEGs that significantly differ between DLB and PDD, and the transcriptomic differences between the two cortical regions. Discussion Although this has been an explorative study, this is the hitherto largest RNA-seq study investigating the transcriptomics of pathology-verified LBD brains. In addition to enhancing our understanding of LBD neurobiology at molecular level, this study has identified specific RNA targets that may be novel biomarkers and therapeutic targets for DLB and PDD. Further replication experiments, and more bioinformatic analyses of our data are on-going. We are currently investigating serum exosomal RNA cargo of people with LBD for evaluating the peripheral biomarker potential of identified DEGs. Translational relevance and therapeutic potential of identified DEGs will be evaluated by in-vitro experiments.