Proton pump inhibitors: predisposers to Alzheimer disease?

The abnormal processing of amyloid-beta peptide (A beta) and resultant formation of fibrillar A beta (fA beta) are major events in the pathogenesis of Alzheimer disease (AD). Microglia as the phagocytic cells of the brain can engulf and digest fA beta within their acidic lysosomes. The lysosomes of AD patients are less acidic and therefore less capable of clearance of fA beta. Vacuolar proton pumps (V-ATPases) which are found abundantly in microglia and macrophages, acidify lysosomes by pumping protons into these structures. Proton pump inhibitors (PPIs) can inhibit V-ATPases of the lysosomes. These drugs are shown to penetrate the blood-brain barrier in animals. PPIs are consumed for long periods in conditions such as gastroesophageal reflux disease, with the resultant exposure of the human brain to the substantial amounts of PPIs. We hypothesize that by blocking the V-ATPases on microglial lysosomes, PPIs may basify lysosomes and hamper degradation of fA beta. Chronic consumption of PPIs may thus be a risk factor for AD.