Network-level organization of systemic inflammation reflects early Alzheimer’s-like behavioral changes

Abstract Systemic immune alterations are increasingly recognized as features of Alzheimer’s disease (AD), yet their network-level organization in preclinical models is poorly understood. We profiled 60 in vivo circulating cytokines and growth factors in young adult TgF344-AD and wild-type rats, reduced the data into five inflammatory profiles via principal component analysis, and mapped these profiles onto protein–protein interaction networks. Multivariate analyses revealed genotype- and sex-dependent network organization, with distinct modules enriched for extracellular matrix-linked interleukin signaling or systemic pro-inflammatory cytokine receptor signaling. Regression analyses controlling for genotype and sex linked these networks to specific behavioral domains: extracellular matrix-associated interleukins predicted altered intertemporal choice, whereas pro-inflammatory cytokine receptor signaling correlated with reduced motivation. These findings provide evidence consistent with systemic inflammatory network remodeling at prodromal stages in a preclinical AD model of AD-like pathology and outline a mechanistically interpretable analytical framework with clear translational potential for integrating peripheral immune signatures with behavioral outcomes across species.