From Correlation to Causation: Cell-Type-Specific Gene Regulatory Networks in Alzheimer’s Disease

INTRODUCTION Alzheimer’s disease (AD) involves complex regulatory disruptions across multiple brain cell types, yet a comprehensive understanding of the intracellular causal mechanisms remains unclear. METHODS We presented an integrative analysis framework using single-nucleus transcriptomic with matched subject-level genotype data from 272 human AD in the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP) study, and constructed causality-based, cell-type-specific gene regulatory networks (GRNs). RESULTS Our method identifies regulatory genes from both transcription factors (TFs) and non-TFs, thereby capturing a complete and accurate causal regulatory map across different brain cell types. This work revealed both established and novel regulations, pathways, and cell-type-unique hub genes in AD. Beyond constructing transcriptome-wide GRNs, we quantitatively assessed hub genes and distinguished those with regulatory or responsive roles. DISCUSSION Our study provides a comprehensive mapping of cell-type-specific causal GRNs in AD, providing a powerful resource for dynamic pathway exploration, hypothesis generation, and functional interpretation.