Insulin resistance as a driver of neuroinflammation and oxidative stress in Alzheimer's disease: Mechanistic links and therapeutic approaches.

Abstract

Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder characterized by the accumulation of amyloid-β plaques and hyperphosphorylated tau protein aggregates, leading to progressive cognitive decline. Growing evidence suggests that AD may also be considered a metabolic disorder closely associated with insulin resistance (IR). Impaired insulin signaling disrupts the PI3K/Akt and GSK3-β pathways, resulting in synaptic dysfunction, neuronal loss, and aberrant protein phosphorylation. Moreover, IR contributes to mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation within the central nervous system (CNS). These metabolic alterations, together with impaired energy homeostasis, dysregulate intracellular signaling cascades and exacerbate amyloid and tau pathology. This narrative review examines the mechanistic interplay among insulin resistance, oxidative stress, and neuroinflammation in AD, with particular emphasis on the shared cellular pathways that underlie disease progression. In addition, it summarizes emerging therapeutic strategies targeting insulin signaling, including pharmacological insulin-sensitizing agents, incretin-based therapies, lifestyle interventions, and bioactive natural compounds. The review also highlights advances in intranasal delivery strategies, which have emerged as a promising approach for enhancing brain targeting and improving therapeutic efficacy. Despite substantial progress, the precise mechanisms linking insulin resistance to neurodegeneration remain incompletely understood. Further mechanistic and translational studies are urgently required to elucidate these interactions and advance the development of effective therapeutic interventions.