In this study we report that the membrane-bound, but not cytosolic insulin degrading enzyme (IDE) protein concentration and IDE activity are significantly decreased in the hippocampal formation of cases affected by mild cognitive impairment (MCI) which are at high risk to develop Alzheimer's disease (AD), relative to normal neurological controls. Membrane-bound IDE protein concentrations and activity in the hippocampal formation continued to decrease during the conversion from MCI to mild–severe AD. This selective decrease in hippocampal membrane-bound, but not cytosolic, IDE concentration and activity was tissue specific since no changes in either membrane-bound or cytosolic IDE were found in the occipital cortex of the same cases examined. Most interestingly, the decreased hippocampal membrane-bound IDE protein activity negatively correlated with brain β-amyloid (Aβ)X-42 content in MCI and in AD brain. The study tentatively suggests that interventions aimed at promoting membrane-bound IDE activities in the brain of MCI cases may help to prevent the onset and possibly the progression into AD through mechanisms involving the clearance of monomeric Aβ from the brain.