In Silico Analyses Suggest That Exercise-Induced Irisin-Mediated Neuroprotection Supports Non-Pharmacological Preventive Strategies for Alzheimer's Disease in Public Health.

Alzheimer's disease (AD) is the leading cause of dementia and imposes a high economic and social burden on healthcare systems. In Brazil, the consistent increase in costs associated with AD hospitalizations, coupled with the absence of curative therapies and population aging, reinforces the need for low-cost, broadly applicable preventive strategies. This study investigated the role of irisin, a myokine induced by physical activity, in the prevention of AD, integrating epidemiological and bioinformatic analyses. Public data on the nutritional status of the Brazilian population in the early 2000s and on AD hospitalizations approximately 20 years later were analyzed, assessing the temporal association using a lagged Spearman correlation. Additionally, genes associated with AD were analyzed through protein-protein interaction networks and functional enrichment. Structural models of irisin and the integrin αV/β5 receptor were employed in molecular docking and molecular dynamics analyses. Historical data indicated a high prevalence of excess weight in the early 2000s (46.7% ± 4.2% of the adult population) and a strong positive correlation with AD hospitalizations two decades later (ρ = 0.88; p = 0.033). Functional analyses revealed enrichment of pathways related to neurodegeneration, neurotrophins, and neuronal plasticity, involving proteins such as BDNF, AKT, ERK1/2, and CREB. Docking and molecular dynamics indicated a stable interaction of irisin with the αV/β5 receptor, suggesting activation of neuroprotective pathways. The findings reinforce physical exercise as a strategic public health tool for the prevention of AD, providing an epidemiological and molecular basis to reduce the future burden of the disease, thereby shifting the focus of public health policy from treatment to prevention.