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 the comprehensive intracellular causal mechanisms remain poorly understood. METHODS: We present an integrative analysis framework using single-nucleus transcriptomics with matched subject-level genotype data from 272 AD patients in the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and construct causality-based, cell-type-specific gene regulatory networks (GRNs). RESULTS: Our method identifies regulatory genes among transcription factors (TFs) and non-TFs, generating a complete and accurate causal regulatory map across brain cell types. Our analyses reveal both established and novel regulations, pathways, and cell-type-specific hub genes in AD. Beyond constructing transcriptome-wide GRNs, we quantitatively evaluate hub genes and distinguish those with regulatory versus responsive roles. DISCUSSION: Our study provides a comprehensive map of cell-type-specific causal GRNs in AD, with a methodology applicable to other complex diseases such as cancer, enabling dynamic pathway exploration, hypothesis generation, and functional interpretation. HIGHLIGHTS: Comprehensive causal regulatory maps across six brain cell types revealed cell-type-specific regulatory mechanisms that move beyond traditional correlation-based and TF-centric model limitations. Novel and established hub genes and functional modules were compared across cell types, providing insights into cellular functions related to AD. Hub gene roles as regulators or targets were quantitatively evaluated within cell-type GRNs. The constructed GRNs show upstream non-TF genes regulating TFs and interconnected TF regulatory modules, highlighting the complexity of AD regulatory mechanisms beyond TF-centric assumptions.