The deposition of beta amyloid is a critical event in the pathogenesis of Alzheimer's disease. This peptide is a metabolite of the amyloid precursor protein. Recent research suggests that there is a correlation between plasma insulin and glucose concentrations and memory performance in Alzheimer's disease sufferers. Additionally, in vitro evidence suggests that both insulin and glucose may affect the metabolism of amyloid precursor protein and therefore the production of beta amyloid--however, to our knowledge no in vivo data have yet been published. We investigated the effect of elevated plasma levels of glucose and insulin on the plasma concentration of amyloid precursor protein in non-Alzheimer's disease subjects. As would be expected following ingestion of a glucose drink, blood insulin and glucose levels significantly increased. Interestingly, however, plasma amyloid precursor protein concentration decreased. Whilst no correlation was observed between insulin or glucose levels and plasma amyloid precursor protein concentration, the decrease in plasma amyloid precursor protein concentration was affected by the apolipoprotein E genotype of the subject. Possession of an epsilon4 allele resulted in a reduced decrease in plasma amyloid precursor protein in response to glucose ingestion when compared to non-epsilon4 subjects. We conclude that glucose ingestion, and the subsequent elevation of plasma levels of glucose and insulin leads to a decrease in plasma amyloid precursor protein concentration. Further studies are required to determine the clinical significance of these physiological changes in plasma amyloid precursor protein and the implications for Alzheimer's disease pathogenesis.