Differential Neuropathology, Genetics, and Transcriptomics in Two Kindred Cases with Alzheimer’s Disease and Lewy Body Dementia

Abstract Background 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. The aim of this study was to define 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, through neuropathological, genetic and transcriptomic comparison of four different brain areas (substantia nigra, hippocampus, parietal lobe and basal ganglia). Results 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. Conclusions 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.