SRP354418 PRJNA796229 GSE193438 Differential Neuropathology, Genetics, and Transcriptomics in two kindred cases with Alzheimer's Disease and Lewy Body Dementia Alzheimer's disease (AD) and Lewy body dementia (LBD) are two different forms of dementia but their pathology may involve the same cortical areas with overlapping cognitive manifestation. Dementia cases within the same family share a common genetic background. Nonetheless, the clinical phenotype may be different due to the different underlying molecular processes that come-up apart from genetics, causing diverse neurodegeneration. Through neuropathological, genetic and transcriptomic comparison of four different brain areas (substantia nigra, hippocampus, parietal lobe and basal ganglia), we defined commonalities and differences in the pathological processes of dementia in two kindred cases, a mother and a son, who developed a classical AD and an aggressive form of AD/LBD respectively. Genetic analysis did not reveal any pathogenic variants in the principal AD/LBD-causative genes. RNA sequencing highlighted high transcriptional dysregulation within the substantia nigra in LBD pathology, while AD underwent lower degree of transcriptional dysregulation, with the parietal lobe being the most involved brain area. Conversely, hippocampus (the most degenerated area) and basal ganglia (lacking specific lesions) expressed the lowest level of dysregulation. Our data suggest that there is a link between the transcriptional dysregulation and the amount of tissue damage accumulated across time, assessed through neuropathology. Moreover, we highlight that the molecular bases of AD and LBD follow very different pathways, which underlie their neuropathological signatures. Indeed, the transcriptome profiling through RNA sequencing may be an important tool in flanking the neuropathological analysis for a deeper understanding of AD and LBD pathogenesis. Overall design: Frozen slices from four brain areas (substantia nigra, hippocampus, parietal lobe and basal ganglia) of the two kindred cases (mother and son) and of the non-demented control were used to perform deep RNA sequencing. GSE193438 pubmed 35884993