Topological influence of immediate-early genes in brain genetic networks and their link to Alzheimer's disease

Immediate-early genes (IEGs), a subset of activity-regulated genes (ARGs), are rapidly and transiently activated by neuronal activity independent of protein synthesis. While extensively researched, the role of IEGs within genetic networks and their potential as drug targets for brain diseases remain underexplored. This study aimed to investigate the topological influence of IEGs within genetic networks and explore their relevance to Alzheimer's disease (AD). To achieve this, we employed a multi-step approach: mouse ARG data were analysed and mapped to human genes to identify the topological properties that distinguish IEGs from other ARGs; the involvement of ARGs in biological pathways and diseases and their mutational constraints were examined; ARG-related variants in AD were assessed using genome-wide association study (GWAS) summary statistics and functional analysis; and network and GWAS findings were integrated to identify ARG-AD-associated genes. Our key findings were: (1) IEGs exhibit significantly higher topological influence across human and mouse gene networks compared to other ARGs; (2) ARGs are less frequently involved in diseases and exhibit higher mutational constraint than non-ARGs; (3) Several AD-associated variants are located in ARG regions, particularly in MARK4 near FOSB, with an AD risk eQTL that increases MARK4 expression in cortical areas; (4) MARK4 emerges as a key node in a dense AD multi-omic network and exhibits a high druggability score. These findings underscore the influential role of IEGs within genetic networks, providing valuable insights into their potential as intervention points for diseases characterised by downstream dysregulation, with MARK4 emerging as a promising and underexplored target for AD. © 2025 The Authors