Molecular mechanisms underlying obesity-induced memory dysfunction: a comprehensive narrative review

Abstract

Obesity has reached epidemic proportions globally and is increasingly recognized as a significant risk factor for cognitive decline and memory impairment. This comprehensive narrative review synthesizes current evidence on the molecular mechanisms underlying obesity-induced memory dysfunction, drawing upon insights from in vivo and in vitro models alongside human clinical and neuroimaging studies. We explore how chronic adiposity triggers a cascade of neuropathological events, beginning with peripheral metabolic dysregulation that propagates to the central nervous system. Key mechanisms include neuroinflammation mediated by pro-inflammatory cytokines and activated microglia, oxidative stress through reactive oxygen species generation, dysregulation of apoptosis pathways, suppression of neurotrophic factors (notably BDNF), neurotransmitter system imbalances, and central insulin resistance. Critically, obesity profoundly impairs hippocampal neurogenesis and synaptogenesis—processes fundamental to memory encoding and consolidation. These pathways exhibit extensive crosstalk, creating self-amplifying cycles that accelerate synaptic loss, neuronal dysfunction, and network disorganization. Emerging therapeutic strategies targeting these mechanisms, including GLP-1 receptor agonists, intranasal insulin, and anti-inflammatory agents, show promise in preclinical and early clinical studies. This review underscores the multifaceted nature of obesity-related cognitive decline and highlights the urgent need for mechanistic, longitudinal human studies to translate these findings into effective clinical interventions against the growing burden of obesity-associated neurodegeneration.