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

Disrupted cell-cell communication represents a fundamental mechanism underlying neurodegeneration, yet how specific intercellular signaling patterns relate to regional brain vulnerability remains poorly understood. Here, we map whole-brain intercellular interaction networks and their spatial correspondence with tissue damage across 13 neurodegenerative conditions, including early- and late-onset Alzheimers disease, presenilin-1 mutations, clinical and pathological subtypes of frontotemporal lobar degeneration, Parkinsons disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. By integrating multiregional single-nucleus and bulk RNA-seq data with curated cell-cell interaction databases and structural MRI, we reconstruct over 1,000 whole-brain maps of ligand-receptor interactions and quantify their associations with regional atrophy patterns. Multivariate analysis identifies three dominant axes of intercellular communication that explain regional vulnerability to neurodegeneration. Notably, the first axis involves neuron-astrocyte-microglia interactions, explaining atrophy patterns shared by frontotemporal lobar degeneration and Alzheimers disease subtypes. Two complementary axes involving neurons, endothelial cells, and astrocytes explain patterns specific to mutations in PS1 and Parkinsons disease. Importantly, validation in an independent post-mortem cohort (N = 375) confirms that late-onset Alzheimers disease-associated cell-cell interactions predict observed frontal cortex atrophy. These results establish a systematic framework linking local intercellular communication networks to spatial patterns of neurodegeneration, revealing both shared and disease-specific molecular pathways that drive regional brain vulnerability and identifying cellular interaction targets for precision therapeutic interventions.