Endogenous neuroprotection in vascular cognitive impairment and dementia

Vascular cognitive impairment and dementia (VCID), affecting millions globally with 30% higher mortality than Alzheimer's disease, lacks effective pharmacotherapies. Microvascular dysfunction emerges decades before clinical symptoms, driving irreversible neurodegeneration once established. Clinical results show that nonpharmacologic interventions demonstrate greater effectiveness: three-fold greater cognitive improvement and five-fold enhanced functional outcomes versus pharmacotherapy, while avoiding adverse effects that affect 40% of patients receiving pharmacological treatments. These interventions orchestrate convergent mechanisms: vascular restoration (reversing vasoconstriction, augmenting perfusion), metabolic reprogramming (mitochondrial/glucose optimisation), neuroinflammation resolution, oxidative stress mitigation, and synaptic preservation. Exercise, neuromodulation, dietary modification, environmental enrichment and conditioning medicine activate multilevel endogenous repair mechanisms inaccessible to pharmacological targeting. This review presents a comprehensive mechanistic framework elucidating how nonpharmacologic strategies modulate interconnected vascular/non-vascular domains. It highlights emerging bioelectronic medicine as a promising disease-modifying therapy, establishing nonpharmacologic interventions as first-line strategies that reconceptualize VCID from intractable neurodegeneration to a preventable, potentially reversible, condition.