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.