Advances in single cell technologies have led to the discovery and characterization of new brain cell-types, that in turn lead to a better understanding of the pathogenesis of Alzheimer’s disease (AD). Here, we present a detailed analysis of single nucleus (sn)RNA-seq data for three stages of AD from middle temporal gyrus (MTG) and compare it with snRNA-seq data from the prefrontal cortices from individuals with alcohol use disorder (AUD). We observed a significant decrease in both inhibitory and excitatory neurons, in general agreement with previous reports. We observed several cell-type specific gene expressions and pathways dysregulations that delineate AD stages. Endothelial and VLMCs (vascular leptomeningeal cells) showed the greatest degree of gene expression changes. Cell-type specific evidence of neurodegeneration was seen in multiple neuronal cell-types particularly in SST (somatostatin) and L5 ET (layer-5 extra-telencephalic) neurons, among others. Evidence of inflammatory responses were seen in non-neuronal cells, particularly in intermediate and advanced AD. We observed common perturbations in AD and AUD, particularly in pathways, like transcription, translation, apoptosis, autophagy, calcium signaling, neuroinflammation, and phosphorylation, that imply shared transcriptional pathogenic mechanisms and support a role for excessive alcohol intake in AD progression. Major AUD gene markers form and perturb a network of genes significantly associated with intermediate and advanced AD. Master regulator analysis from AUD gene markers revealed significant correlation with advanced AD of transcription factors that have implications in intellectual disability, neuroinflammation, and other neurodegenerative conditions, further suggesting a shared nexus of transcriptional changes between AD and AUD.Significance StatementThis study holds significant implications for understanding the intricate molecular landscape of Alzheimer's disease (AD) and its intersection with alcohol use disorder (AUD). By profiling transcriptional changes in the neocortex associated with AD progression and comparing them with those in AUD, we shed light on shared gene expression and pathway dysregulations between the two conditions. Our findings corroborate prior research on neuronal depletion and highlight novel insights into cell-type-specific gene expression patterns in AD stages. Moreover, the identification of common genetic signatures suggests a potential exacerbating effect of AUD on AD progression. This comprehensive analysis not only deepens our understanding of AD pathology but also underscores the importance of considering AUD as a potential risk factor for accelerating AD onset or severity.
