New dementia red flag issued for PPIs

This highly effective drug class has been linked to other conditions such as infections and even lupus.

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Using proton pump inhibitors for at least four years could mean a 33% higher risk of developing dementia compared to people who don’t use the medications, new research has found. 

And while the researchers said more study was needed to understand the possible pathways between cumulative PPI use and the development of dementia, an Australian expert said the findings were a concern and doctors should exercise caution around long-term PPI prescribing. 

UNSW Scientia Professor Kaarin Jane Anstey, an expert in dementia risk reduction and epidemiology, told The Medical Republic that the research highlighted the problem was not necessarily with the PPI itself but the length of time it was used. 

“It is the long-term use that is problematic and not short-term,” she said. 

“This means there needs to be a review of PPI usage, and evaluation of whether there are alternative medications for people who need treatment long term.” 

The US study of 5700 people, age 45 and older and without dementia at the start of the study, tracked drug use and dementia diagnoses over almost six years. Participants had an average age of 75. 

The paper, published in Neurology, found that a quarter of participants had taken PPIs, and 585 people developed dementia.  

After adjusting for factors such as age, sex and race, as well as health-related factors such as high blood pressure and diabetes, researchers found people who had been taking acid reflux drugs for more than 4.4 years had a 33% higher risk of developing dementia than people who never took the drugs. 

They did not find a higher risk of dementia for people who took the drugs for fewer than 4.4 years. 

Professor Anstey, who was not involved in the study, said “the findings are of concern because PPIs are widely used”. 

“The findings of the cumulative effect need to be replicated but this is not the first time an increased risk of dementia has been associated with PPIs,” she said. 

PPIs have also been associated with risk in other conditions like drug-induced lupus, bacterial enteric infections with C. difficile, salmonella and campylobacter, childhood asthma and cardiovascular conditions.  

Study author Associate Professor Kamakshi Lakshminarayan, neurologist at the University of Minnesota in the US, speculated on plausible pathways underpinning the link, including vitamin B12 deficiency and impaired amyloid metabolism.  

“We are unable to comment on participant B12 levels in our dataset. However, adjusting for participant baseline B12 use did not alter the results on the relation between PPI use and dementia in our data,” Professor Lakshminarayan and colleagues wrote. 

“In experimental mice models, PPI use has been associated with an increase in beta-amyloid levels in the brain. PPIs may modify the gamma-secretase enzyme which cleaves a precursor protein to beta-amyloid. This contributes to the development of Alzheimer’s disease by increasing beta-amyloid plaques within the brain. 

“Another pathway is via vascular causes. PPIs have been implicated in the development of other health outcomes including stroke and chronic kidney disease.” 

Professor Anstey said that while the study used well-accepted dementia diagnosis criteria there were some limitations, including the fact there was no verification of the amount of PPIs taken through blood testing.  

“Over-the-counter drugs were not included, and PPIs were sold over the counter in the US from 2003, which was prior to the study assessments, so we don’t know if there were participants who had long term use who were not captured in the analysis,” she said. 

“Medication use was also obtained from self-report by phone or at study visits.” 

Neurology 2023, online 9 August