Whole-Brain Cell-Cell Interaction Axes Explaining Tissue Vulnerability Across the Neurodegenerative Spectrum

Cell-cell communication is essential for proper brain functioning and health. Here, we characterize whole-brain patterns of cellular interactions that spatially align with tissue damage across 13 neurodegenerative conditions, including early- and late-onset Alzheimer's disease (EOAD, LOAD), presenilin-1 mutations (PS1), frontotemporal lobar degeneration, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and amyotrophic lateral sclerosis (ALS). By integrating spatial gene expression with structural MRI data, we created over 1,000 whole-brain maps of ligand-receptor interactions. Multivariate analysis revealed three principal axes of cell-cell communication underlying brain tissue vulnerability. The first axis involved neuron-astrocyte-microglia interactions, explaining atrophy patterns shared by frontotemporal lobar degeneration and Alzheimer's disease subtypes. Moreover, the first axis was enriched with genes involved in regulation or spreading of amyloid beta/tau and/or Alzheimer's disease risk. Two complementary axes involving neurons, endothelial cells, and astrocytes explained patterns specific to PS1 and PD. Notably, we confirmed that cell-cell interactions identified for LOAD were also associated with frontal cortex atrophy in 375 participants from an independent database. These findings reveal both distinctive and shared molecular signaling pathways underlying tissue vulnerability across neurodegenerative disorders, clarifying disease mechanisms and highlighting potential cellular targets for therapeutic interventions.