Probing molecular pathways: Illuminating the connection between COVID‐19 and Alzheimer's disease through the endocannabinoid system dynamics

Abstract Our study investigates the molecular link between COVID‐19 and Alzheimer's disease (AD). We aim to elucidate the mechanisms by which COVID‐19 may influence the onset or progression of AD. Using bioinformatic tools, we analyzed gene expression datasets from the Gene Expression Omnibus (GEO) database, including GSE147507, GSE12685, and GSE26927. Intersection analysis was utilized to identify common differentially expressed genes (CDEGs) and their shared biological pathways. Consensus clustering was conducted to group AD patients based on gene expression, followed by an analysis of the immune microenvironment and variations in shared pathway activities between clusters. Additionally, we identified transcription factor‐binding sites shared by CDEGs and genes in the common pathway. The activity of the pathway and the expression levels of the CDEGs were validated using GSE164805 and GSE48350 datasets. Six CDEGs (MAL2, NECAB1, SH3GL2, EPB41L3, MEF2C, and NRGN) were identified, along with a downregulated pathway, the endocannabinoid (ECS) signaling pathway, common to both AD and COVID‐19. These CDEGs showed a significant correlation with ECS activity ( p < 0.05) and immune functions. The ECS pathway was enriched in healthy individuals' brains and downregulated in AD patients. Validation using GSE164805 and GSE48350 datasets confirmed the differential expression of these genes in COVID‐19 and AD tissues. Our findings reveal a potential pathogenetic link between COVID‐19 and AD, mediated by CDEGs and the ECS pathway. However, further research and multicenter evidence are needed to translate these findings into clinical applications.