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

Abstract

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 manifestations. Nonetheless, the clinical phenotype is different due to the topography of the lesions driven by the different underlying molecular processes that arise apart from genetics, causing diverse neurodegeneration. Here, we define the commonalities and differences in the pathological processes of dementia in two kindred cases, a mother and a son, who developed classical AD and an aggressive form of AD/LBD, respectively, through a neuropathological, genetic (next-generation sequencing), and transcriptomic (RNA-seq) comparison of four different brain areas. A 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 the AD/LBD case, while the AD case showed lower transcriptional dysregulation, with the parietal lobe being the most involved brain area. The 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 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.

Dementia with Lewy Bodies: Genomics, Transcriptomics, and Its Future with Data Science

“…The expression of cholinergic receptors, CHRM1 and CHRM4, have also been shown to be upregulated in AD when compared to DLB [102]. Further research has demonstrated that the transcriptomic differences between AD and those with Lewy pathology is dependent on brain region [103]. Transcriptional dysregulation appears to correlate with neurodegeneration, and individuals with Lewy pathology are likely to experience dysregulation in the substantia nigra, whilst cases of AD are more likely to show dysregulation in the parietal lobe [103].…”

“…Further research has demonstrated that the transcriptomic differences between AD and those with Lewy pathology is dependent on brain region [103]. Transcriptional dysregulation appears to correlate with neurodegeneration, and individuals with Lewy pathology are likely to experience dysregulation in the substantia nigra, whilst cases of AD are more likely to show dysregulation in the parietal lobe [103]. Further research is warranted to determine how DLB differs from other dementias and synucleinopathies across the brain region to improve molecular understanding and facilitate accurate diagnosis.…”

Gene therapy for Parkinson’s Disease and Ethical Challenges: A Systematic Review

“…Alzheimer's disease, for example, is caused by a number of genetic mutations and epigenetic regulations. (PSEN1; PSEN2; APP; APOE ε4; TREM2; SORL1; ABCA7; CR1; DAPK1; CLU; PICALM; BIN1; MS4A6A; CD33; CD2AP; EPHA1; miR-124; miR-15 et miR-146a) [8] and Lewy body dementia (LBD) (GBA, SNCA, APOE, CNTN1, BCL7C/STX1B, T. M. Zohoncon SCARB2 [9], miR-24-3p, miR-25-3p, miR-3p, miR-361-5p, miR-425x5p, et miR-451a [10]. Whereas Huntington's disease is caused by an expansion of the polymorphic CAG trinucleotide by more than 35 repeats in exon 1 of the HTT gene [11].…”