Inference of Cell-Cell Communication to Understand the Molecular Mechanisms of Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder that affects around 55 million older adults worldwide. However, the molecular and cellular mechanisms of AD are poorly understood. The complex interactions between brain cells are critical for maintaining brain function and homeostasis, as well as playing an important role in the cellular response to neurodegenerative diseases. Nevertheless, the disrupted intercellular communication between neural, non-neural, and neighboring cells in AD remains largely unexplored. In this study, we investigated perturbations in cell-cell communication, and its dysregulation across different stages of the disease, to better understand the underlying mechanisms of AD. Using single-nuclei RNA-sequencing data from over 2.3 million nuclei in the prefrontal cortex of 427 ROSMAP participants (115 non-AD/early-AD, 198 intermediate-AD, and 114 late-AD), we applied LIANA (an open-source LIgand-receptor ANalysis frAmework) to predict cell-cell communication between brain cells, immune cells, and brain-immune communication. We identified 214 significant ligand-receptor interactions across 29 cell-type pairs and highlighted cell-type-specific perturbations of interactions such as RTN4-LINGO1, APP-LRP6, and ADAM10-TSPAN14. Our functional analysis revealed key pathways that are dysregulated in AD, including calcium signaling, neurogenesis, cell migration, and immune response. We also identified potential therapeutics using the Therapeutic Target Database. Our findings present promising directions for future drug development for treating Alzheimer's disease.