Mechanism May Explain Increased Risk Of Dementia

"We've been able to show that proton pump inhibitors affect the synthesis of the neurotransmitter acetylcholine, which plays a significant part in conditions such as Alzheimer's disease," says Taher Darreh-Shori, senior researcher at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet. "Since there's no effective treatment for the disease, it's important to avoid risk factors. We therefore want to draw attention to this so that the drugs aren't used needlessly for a long time."

PPIs work by blocking pumps that transport acidic hydrogen ions from cells that form the mucosa, when they are blocked there is a reduction in acid and the corrosive damage done to tissues. Studies suggest that there are higher rates of dementia among those who use PPIs but the connection was unclear, until now.

3D computer simulations were first used to examine how 6 PPI variants based on different active substances interact with choline acetyltransferase enzymes that function to synthesize the neurotransmitter acetylcholine needed for passing signals among nerve cells. Simulations showed that the drugs were able to bind with the choline acetyltransferase enzymes. 

Next the binding effect was analyzed which revealed that all of the drugs inhibited the enzyme resulting in reduced production of acetylcholine, wherein the stronger the binding the stronger the inhibitory effect was observed; drugs based on the substances omeprazole, esomeprazole, tenatoprazole and rabeprazole had the strongest affinity and were the strongest inhibitors, while the variants pantoprazole and lansoprazole were the weakest. 

Additional research is required to examine whether these results are representative of what occurs within the human body. However, based on these observations Darreh-Shori is advising against the overuse of proton pump inhibitors. 

"Special care should be taken with the more elderly patients and those already diagnosed with dementia," he says. "The same also applies to patients with muscle weakness diseases such as ALS, as acetylcholine is an essential motor neurotransmitter. In such cases, doctors should use the drugs that have the weakest effect and prescribe them at lowest dose and for as short a time as possible." Darreh-Shori adds, "I would, however, like to stress that the correct use of the drugs is safe also in the elderly, as long as the drugs are used for a limited time and when they're really needed, as our nervous system is pretty flexible when it comes to tolerating short-term impact.”