Systematic identification of cell-cell interactions associated with the severity of patients with Alzheimer's disease.

BackgroundAlzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder involving dysfunction across multiple brain regions. While accumulating evidence has implicated the roles of diverse cell types, including neurons, glia, and vascular cells in AD pathogenesis, it is still poorly understood how cell type interactions drive or respond to the disease progression and severity.ObjectiveThis study aimed to systematically characterize cell-type-specific alterations and intercellular communication changes associated with AD progression.MethodsWe leveraged the transcriptome profiling and a previously established statistical framework to present a comprehensive mapping of the cellular interaction landscape in the human brain of AD.ResultsWe identified a wide array of AD-associated cell-cell interactions (CCIs), including not only between the non-neuronal and neuron cells, but also among different neuron subtypes. These patterns were further supported by cell-type signature scoring. Moreover, due to the flexibility of the framework, we further examined CCIs associated with clinical dementia rating across multiple cortical regions. Our findings revealed that the temporal and frontal cortices showed a stronger correlation with dementia severity. However, the subregions of the temporal area show specific dementia-associated CCIs, especially between the inferior and middle temporal gyrus.ConclusionsOur work advances our understanding of the cellular microenvironment in AD, offering novel insights into how intercellular interactions shape disease trajectory and cognitive outcomes.