Alzheimer's disease rewires gene coexpression networks coupling different brain regions

Connectome studies have shown how Alzheimer's disease (AD) disrupts functional and structural connectivity among brain regions. But the molecular basis of such disruptions is less studied, with most genomic/transcriptomic studies performing within-brain-region analyses. To inspect how AD rewires the correlation structure among genes in different brain regions, we performed an Inter-brain-region Differential Correlation (Inter-DC) analysis of RNA-seq data from Mount Sinai Brain Bank on four brain regions (frontal pole, superior temporal gyrus, parahippocampal gyrus and inferior frontal gyrus, comprising 264 AD and 372 control human post-mortem samples). An Inter-DC network was assembled from all pairs of genes across two brain regions that gained (or lost) correlation strength in the AD group relative to controls at FDR 1%. The differentially correlated (DC) genes in this network complemented known differentially expressed genes in AD, and likely reflects cell-intrinsic changes since we adjusted for cell compositional effects. Each brain region used a distinctive set of DC genes when coupling with other regions, with parahippocampal gyrus showing the most rewiring, consistent with its known vulnerability to AD. The Inter-DC network revealed master dysregulation hubs in AD (at genes ZKSCAN1, SLC5A3, RCC1, IL17RB, PLK4, etc.), inter-region gene modules enriched for known AD pathways (synaptic signaling, endocytosis, etc.), and candidate signaling molecules that could mediate region-region communication. The Inter-DC network generated in this study is a valuable resource of gene pairs, pathways and signaling molecules whose inter-brain-region functional coupling is disrupted in AD, thereby offering a new perspective of AD etiology.