Type 2 diabetes mellitus (T2DM) increases vulnerability to cognitive decline through interacting disturbances in insulin signaling, mitochondrial energetics, redox and lipid homeostasis, neuroimmune regulation, neurovascular coupling, and experience-dependent plasticity. This review integrates molecular, cellular, preclinical, and clinical evidence linking these processes to altered gene expression, glial dysfunction, synaptic instability, and impaired cognition. We distinguish well-supported mechanisms from unresolved questions concerning causality, cell-type specificity, human hippocampal remodeling, context-dependent pharmacological effects, and the translational limitations of experimental models. On this basis, we propose an integrative framework in which metabolic flexibility acts as a permissive gatekeeper for neural adaptation. AMPK-centered signaling supports mitochondrial quality control, autophagy, antioxidant defenses, and restraint of NF-kB/NLRP3-associated inflammation, but is considered necessary rather than sufficient for cognitive recovery. Durable plasticity additionally requires activity-dependent CREB-BDNF signaling and adequate neurovascular support to match energy delivery with circuit demand. Exercise, cognitive training, environmental enrichment, metformin, and incretin-based therapies engage complementary components of this network, although their efficacy is likely to vary with age, metabolic state, inflammatory burden, vascular reserve, treatment timing, and adherence. The framework predicts that metabolic activation without circuit engagement will provide limited cognitive benefit, whereas plasticity-promoting interventions will be constrained by persistent metabolic or vascular dysfunction. We therefore argue for multimodal, biomarker-informed strategies that integrate metabolic stabilization, vascular support, and structured physical and cognitive stimulation. Long-term randomized studies combining neuroimaging with molecular and metabolic profiling are required to test these predictions and define precision approaches for preserving cognitive resilience in T2DM.
