Long-term use of proton pump inhibitors was significantly associated with later diagnoses of dementia in adults aged 75 years and older in a prospective cohort study of more than 73,000 individuals. The findings were published online Feb. 15 in JAMA Neurology.

Overall, the risk of incident dementia was 44% higher among the 2,950 patients who received regular proton pump inhibitors, compared with 70,729 who didn’t receive PPIs (hazard ratio of 1.44), according to Willy Gomm, Ph.D., of the German Center for Neurodegenerative Diseases in Bonn, and his colleagues.

To assess the potential link between PPIs and dementia, the researchers reviewed data from a German insurance database during 2004-2011. The study population included 73,679 community-dwelling adults aged 75 years and older who were free of dementia at the start of the study (JAMA Neurol. 2016 Feb 15. doi: 10.1001/jamaneurol.2015.4791 ). The patients taking PPIs were slightly but significantly older than those not taking PPIs and had a higher proportion of women (P less than .001 for both). PPI users were also significantly more likely than nonusers to have a history of depression, stroke, coronary disease, and use of polypharmacy (P less than .001 for each).

The risk of incident dementia decreased with age, from 69% for patients aged 75-79 years to 49% among those 80-84-years and 32% among those aged 85 years and older.

In addition, the risk of dementia was not significantly different based on specific drug in a subgroup analysis of the three most often prescribed PPIs, omeprazole, pantoprazole, and esomeprazole, for which the hazard ratios were 1.51, 1.58, and 2.12, respectively.

“If PPIs have adverse effects, it is important to be aware of them,” Dr. Daniel E. Freedberg of Columbia University, New York, said in an interview. “When PPIs are indicated, the preponderance of data indicate that their benefits outweigh their potential risks,” he added. “Clinicians should reassure patients that this was a single study and that previous studies have reached different conclusions. Clinicians should focus on whether or not PPIs are indicated rather than on PPI side effects.”

Dr. Freedberg also noted several key limitations of the study.

“First, the authors were unable to adjust for crucial variables that might explain a noncausal link between PPIs and dementia. For example, lower socioeconomic status is an established predictor of dementia and may also be associated with PPI use. However, the authors could not capture socioeconomic status.

“Second, patients who use PPIs have more frequent and more intensive health care interactions than patients who do not use PPIs. These patients are thus also more likely to be diagnosed with dementia. This is another source for bias that the authors were not able to capture. Third, clinicians should be aware that this study was designed to compare extremes of PPI use,” Dr. Freedberg emphasized.

In addition, “In the primary analysis, patients were classified as exposed to PPIs only if they received at least one PPI prescription every 3 months for an 18-month period. Patients who used occasional PPIs were excluded from the study,” said Dr. Freedberg.

“The present study can only provide a statistical association between PPI use and risk of dementia,” the researchers noted. “The possible underlying causal biological mechanism has to be explored in future studies,” they wrote.

The researchers had no financial conflicts to disclose.