Epidemiological studies reveal that metabolic disorders, and specifically type 2 diabetes (T2D), are relevant risk factors to develop Alzheimer's disease (AD) and vascular dementia (VaD), the most common causes of dementia. AD patients are in a tremendous need of new therapeutic options because of the limited success of available treatments. Natural polyphenols, and concretely Mangifera indica Linn extract (MGF), have been reported to have antiinflammatory, antioxidant and antidiabetic activities. The role of MGF in central complications associated with T2D, after long-term treatment of db/db mice with MGF was analyzed. Metabolic parameters (body weight, glucose and insulin levels) as well as central complications including brain atrophy, inflammatory processes, spontaneous bleeding, tau phosphorylation and cognitive function in db/db mice treated with MGF for 22 weeks were assessed. MGF limits body weight gain in obese db/db mice. Insulin and C-peptide levels, indicative of pancreatic function, were longer maintained in MGF-treated animals. MGF reduced central inflammation by lowering microglia burden, both in the cortex and the hippocampus. Likewise, central spontaneous bleeding was significantly reduced in db/db mice. Cortical and hippocampal atrophy was reduced in db/db mice and tau hyperphosphorylation was lower after MGF treatment, resulting in partial recovery of learning and memory disabilities. Altogether, the data suggested that MGF treatment may provide a useful tool to target different aspects of AD and VaD pathology, and could lead to more effective clinical therapies for the prevention of metabolic related central complications associated with AD and VaD.