Cell-cell communication analysis demonstrates early-stage common pathways linking ageing, Alzheimers disease, and Type 2 diabetes-related brain dysfunction

Ageing promotes to the development of age-related diseases and cognitive decline. In this study, we integrated and analysed four single-cell RNA sequencing (scRNA-seq) datasets encompassing Alzheimers disease, type 2 diabetes, and ageing in mouse brain tissue to identify early pathological factors that may drive normal ageing toward disease through alterations in cell-cell communication (CCC). Building on our previously established CCC change modelling framework, we found that both Alzheimers disease and ageing were characterized by a loss of intercellular communication, whereas type 2 diabetes exhibited an overall gain of new communication pathways. Notably, vascular communication changes were more prominent in age-related diseases than in normal ageing. Furthermore, we identified a series of CCC molecules that play key roles in brain ageing and disease through pseudo covariance and conflicting resolving CCC algorithms. Among them, the LRP1 receptor on astrocytes emerged as a central CCC hub implicated in both ageing and disease pathology.