Proton pump inhibitors act with unprecedented potencies as inhibitors of the acetylcholine biosynthesizing enzyme—A plausible missing link for their association with incidence of dementia

Abstract

Introduction: Several pharmacoepidemiological studies indicate that proton pump inhibitors (PPIs) significantly increase the risk of dementia. Yet, the underlying mechanism is not known. Here, we report the discovery of an unprecedented mode of action of PPIs that explains how PPIs may increase the risk of dementia. Methods: Advanced in silico docking analyses and detailed enzymological assessments were performed on PPIs against the core-cholinergic enzyme, choline-acetyltransferase (ChAT), responsible for biosynthesis of acetylcholine (ACh). Results: This report shows compelling evidence that PPIs act as inhibitors of ChAT, with high selectivity and unprecedented potencies that lie far below their in vivo plasma and brain concentrations. Discussion: Given that accumulating evidence points at cholinergic dysfunction as a driving force of major dementia disorders, our findings mechanistically explain how prolonged use of PPIs may increase incidence of dementia. This call for restrictions for prolonged use of PPIs in elderly, and in patients with dementia or amyotrophic lateral sclerosis.