Down syndrome (DS) individuals are characterized by a variety of pathological phenotypes that manifest with wide variability in different tissues. In the central nervous system, the accelerated aging phenotype is associated with the risk of developing Alzheimer-like dementia. A central aspect of neurodegeneration is the close association between metabolic disorders and cognitive decline. Multiple studies have suggested a link between metabolic disorder and microRNAs (miR), small non-coding RNAs acting as post-transcriptional regulators of a plethora of genes. Among triplicated miRNAs on chromosome 21, we focus on miR-802 because exists an association with development of insulin resistance (IR) in obesity and diabetes. The goal of the study is to decipher how miR-802 may contribute to aberrant insulin signaling (IS) and to develop dementia in DS. The miR-802 expression and activation state of main components of the IS were evaluated: in the brain of autoptic cases from DS, DSAD and from Ts65Dn mice (a model of DS). Using bioinformatic tools we identified miR-802 predicted target genes involved in the IS (PTEN and GSK-3β). The IS alterations worsen in the transition from DS to DS/AD and similar findings were collected inTs65Dn mice, where IS dysregulation persists with aging and is associated to neurodegeneration. Intriguingly, these latter changes were driven by the over-expression of miR-802, which negatively regulates PTEN and GSK-3β mRNA in the brain. In this picture, the identification of specific targets modulated by miR-802 and involved in IS pathway, will provide molecular basis to prevent/delay the onset of brain IR in DS.