Immediate-early genes: Key influencers in genetic networks and their role in Alzheimer’s disease

Immediate-early genes (IEGs) are a class of activity-regulated genes (ARGs) that are transiently and rapidly activated in the absence of de novo protein synthesis in response to neuronal activity. We explored the role of IEGs in genetic networks to pinpoint potential drug targets for Alzheimer’s disease (AD). Using a combination of network analysis and genome-wide association study (GWAS) summary statistics we show that (1) IEGs exert greater topological influence across different human and mouse gene networks compared to other ARGs, (2) ARGs are sparsely involved in diseases and significantly more mutational constrained compared to non-ARGs, (3) Many AD-linked variants are in ARGs gene regions, mainly in MARK4 near FOSB, with an AD risk eQTL that increases MARK4 expression in cortical areas, (4) MARK4 holds an influential place in a dense AD multi-omic network and a high AD druggability score. Our work on IEGs’ influential network role is a valuable contribution to guiding interventions for diseases marked by dysregulation of their downstream targets and highlights MARK4 as a promising underexplored AD-target.