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15 June 2020 - Karolinska Institute - New findings explain how 'indigestion' medications can increase dementia risks

Karolinska Institute


Millions of people around the world use proton pump inhibitors for conditions like heartburn, gastritis and stomach ulcers. Researchers at Karolinska Institutet in Sweden now report that the long-term use of these drugs could increase the risk of developing dementia.


Striking new findings show that 'proton pump inhibitors' (PPIs) - popular 'antacid' medications widely prescribed for indigestion, acid reflux ('heartburn') or other gastric symptoms, and also available as over-the-counter medications - could increase risks for dementia and other mental health problems. See:

Researchers found these drugs reduced production of a key brain signalling chemical - acetylcholine - which plays fundamental roles in both cognition and movement. 

Very few drugs have ever been shown to help in managing Alzheimers's disease or other forms of dementia - but ironically enough, the few that have include 'acetylcholinesterase inhibitors'. These help to slow the breakdown of acetylcholine, with the aim of maintaining the levels needed to support normal cognition and movement.

By reducing stomach acid, PPIs and other antacid medications are already known to increase risks for Vitamin B12 deficiency - which can also cause serious neurological and mental health problems, including dementia.  See:  

These latest findings - showing that PPIs reduce acetylcholine - were based on laboratory studies. So as the researchers noted, these negative effects have not yet been proven to happen in humans

But longitudinal studies HAVE already shown that PPI-users are at increased risk of developing dementia. 
 And there are now at least two highly plausible mechanisms that could explain why that link might be a causal one.

Meanwhile, for information on DIETARY CHOLINE - a key brain nutrient needed to make acetylcholine (among many other things) but one which is seriously lacking from many people's diets, see:

And for more information on the importance of B VITAMINS (along with omega-3 fatty acids) for healthy brain ageing, see:

The results from this new Karolinska institute study are published in the journal Alzheimer's & 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."

Proton pump inhibitors (PPIs) work by blocking the pumps that transport acidic hydrogen ions from the cells that form the mucosa. When the pumps are out of action, there is a reduction in acid, and ultimately, the corrosive damage it does to tissue. Population studies have previously shown higher rates of dementia in people using PPIs, but the connection was unclear until now.

First, the researchers used 3-D computer simulations to examine how six PPI variants based on different active substances interacted with an enzyme called choline acetyletransferase, the function of which is to synthesize the neurotransmitter acetylcholine.

As a neurotransmitter, acetylcholine is needed for passing signals among nerve cells, but this only works if enough of the substance is produced. The simulations showed that all the tested drugs were able to bind with the enzyme.

The researchers then analyzed the effect of this binding. They found that all the drugs inhibited the enzyme, resulting in a reduced production of acetylcholine, where the stronger the binding, the stronger the inhibitory effect.

Drugs based on the active substances omeprazole, esomeprazole, tenatoprazole and rabeprazole had the greatest affinity and were therefore the strongest inhibitors of the enzyme, while the variants pantoprazole and lansoprazole were the weakest (see illustration).

Complementary studies are now needed to examine whether these laboratory observations represent what occurs in the body. However, Darreh-Shori is already advising against the overuse of PPIs.

"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."

"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," he adds.