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The use of proton pump inhibitors (PPIs) for the treatment of acid-related upper gastrointestinal conditions, including gastroesophageal reflux disease and peptic ulcer disease, has grown rapidly over the past two decades. This rise has prompted concerns about possible adverse effects on health, including a higher risk of bone fractures and even an increase in mortality risk, although the latter has been shown to be .

Previous research has also suggested that PPI use may be linked to an increased risk of dementia, with a recent reporting a 27% increase in Alzheimer's disease risk. Such concerns have impacted about PPIs.

However, these studies were limited by incomplete assessment of medication use, a failure to account for confounders, and their reliance on claims-based diagnoses of dementia, which can lead to misclassification.

To clarify any potential association, Andrew T. Chan, MD, MPH, of Harvard Medical School and Massachusetts General Hospital in Boston, and colleagues analyzed data on PPI use in a large cohort of older adults from the trial.

Chan discussed the findings, recently published in , in the following interview with the Reading Room.

Why this study now?

Chan: PPIs are among the most commonly used medications worldwide. Over the last several years, there have been well-publicized studies that have alarmingly linked chronic use of these medications with long-term health complications, such as dementia. We had a working hypothesis that studies detecting such associations may have been picking up signals due to confounding by the reason why people were using these drugs or other health factors associated with both taking the drugs and these long-term complications.

What had previous research shown about the possible link? How robust was it?

Chan: Previous studies focused on PPI use and the risk of a diagnosis of end-stage dementia, some of which showed an association. However, these studies had substantial limitations associated with the inability to account for risk factors, such as polypharmacy or medical comorbidities more commonly seen in individuals who take PPIs, and these likely contributed to dementia.

In addition, these studies were also limited in their ability to ascertain true dementia diagnoses. It is quite possible that PPI use may also be associated with the likelihood of receiving a dementia diagnosis rather than being truly related to the disease. Thus, there was a high unmet need for studies that specifically looked at the association of PPI use with objective measures of cognitive decline and dementia.

What was thought to be the probable mechanism/pathway for the deleterious impact?

Chan: There has been a range of theories, including alterations in the ability to absorb micronutrients relevant to neurologic function.

Is it common, then, for U.S. seniors to resist taking PPIs for fear of cognitive decline?

Chan: Although there are no data to suggest that this concern has motivated older adults to stop taking PPIs, we certainly have seen anecdotal evidence from clinicians who have had patients raise this issue in the clinic.

Who made up the study cohort and would results from this cohort be applicable to the broader U.S. population?

Chan: The cohort comprised nearly 19,000 adults ages 65 to 70 years in Australia and the U.S. Although the cohort was largely white, in the subset of U.S. participants who were African American or Latino American, the results appeared similar. So we do think that the results from this large cohort are likely generalizable to the general population, but additional studies in other more diverse populations are warranted.

What were the main findings and were they unexpected given previous research?

Chan: We did not find any association between PPI use and risk of dementia or cognitive impairment based on annual cognitive testing conducted over more than 6 years of follow-up -- not with baseline, new, and ongoing use. These results did not surprise us, given that we overcame many of the limitations of prior studies. We were able to do a more detailed assessment of potential confounding factors, as well as apply more objective assessments of cognition, thereby minimizing biases related to the likelihood of receiving a dementia diagnosis associated with taking PPIs.

How do the results clarify the clinical picture?

Chan: These data should provide reassurance that PPI use is not associated with long-term risk of cognitive decline or dementia.

Given the unique data, large sample size from ASPREE, and rigorous methodology employed in this study, providers can cite these data to show patients, especially older adults, that reports of the association between longer-term PPI use and dementia are unlikely to be true.

What is your best takeaway message for gastroenterologists?

Chan: Although we should periodically reassess whether PPI use is warranted for any of our patients on chronic treatment, these data suggest that for the right patient and for the right indication, long-term use of PPIs is generally safe with respect to long-term cognition.

You can read the abstract of the study here, and about the clinical implications of the study here.