As a first of its kind study, a team of researchers at Karolinska Institutet uncovered a mode of action explaining how long-term use of proton pump inhibitors may increase the risk of dementia. Their findings appeared in Alzheimer’s & Dementia.
“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),” according to the study’s co-authors.
For the study, the research team utilized three-dimensional computer simulations to test how six PPI variants interacted with choline acetyltransferase. The effect of the binding between the tested drugs and the enzyme was then analyzed.
In the findings, all the drugs tested inhibited the enzyme and decreased acetylcholine in the brain. Strong binding led to a more profound inhibitory effect, researchers say.
From the findings: “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.”
“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,” researchers concluded. “This call for restrictions for prolonged use of PPIs in elderly, and in patients with dementia or amyotrophic lateral sclerosis.”
