The epidemiological finding of an increased risk of dementia in patients with diabetes mellitus has raised the hypothesis that a dysfunction of the insulin receptors plays a role in the pathogenesis of Alzheimer's disease (AD). A possible link is suggested by the evidence that the insulin-stimulated phosphatidylinositol-3-kinase (PI-3-K)/phospho-Akt pathway negatively controls the glycogen synthase kinase-3β. The activation of this enzyme mediates the hyperphosphorylation of the tau protein, a relevant step in the formation of the neurofibrillary tangles associated with AD. We hypothesized that the neurodegeneration associated with AD is related to an impairment of the intracellular signalling stimulated by insulin receptors. To test this hypothesis we assessed the PI-3-K/phospho-Akt pathway following in-vitro challenge with insulin in peripheral blood mononuclear cells from subjects with AD (n = 20) and controls (n = 20). We found that the stimulation of PI-3-K is blunted in patients with AD with respect to control. The reduction did not correlate with the extent of cognitive decline or with scores at neuropsychological tests exploring attention, memory, language or visuospatial abilities. The study supports the hypothesis that an impaired control of glycogen synthase kinase-3β activity by insulin receptor-mediated signalling plays a role in the pathogenesis of AD, facilitating tau protein phosphorylation and neurofibrillary tangle formation.