PPIs and Dementia: A Tale of Two Studies – Part One

PPIs and Dementia: A Tale of Two Studies – Part One

Prateek Sharma, MD, FASGE, reviewing Mehta RS, et al. Gastroenterology 2023 Sep.

Previous research has suggested a potential connection between proton pump inhibitors (PPIs) and a higher risk of dementia, causing concern among patients and health care professionals. Many of these studies relied on diagnosis codes to identify cases of dementia and were constrained by incomplete evaluations of PPI usage, as these medications are frequently accessible without a prescription. Two recently published studies have evaluated the association between PPI use and dementia—with divergent conclusions.

This post hoc analysis used data from the ASPREE trial (ASPirin in Reducing Events in the Elderly), which included 18,934 adults aged 65 years or older from the United States and Australia. The study aimed to investigate the potential associations between the use of PPIs and histamine-2 receptor antagonists (H2RAs) and dementia and cognitive impairment.

Participants‘ baseline and recent usage of PPIs and H2RAs were assessed during annual in-person study visits. The presence of incident dementia was defined based on criteria from the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition. Secondary endpoints included cognitive impairment, no dementia (CIND), and changes in cognitive function. The relationships between medication use and dementia and CIND outcomes were analyzed using Cox proportional hazards models, while changes in cognitive test scores were assessed using linear mixed-effects models.

The results of the analysis revealed that baseline PPI use was not linked to an increased risk of incident dementia (multivariable hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.72-1.08), CIND (multivariable HR, 1.00; 95% CI, 0.92-1.09), or changes in overall cognitive test scores over time (multivariable coefficient, -0.002; P=.85). Similarly, no significant associations were observed between the use of H2RAs and any of the examined cognitive endpoints.

Prateek Sharma, MD, FASGE


There is no substantial evidence linking the use of PPI medications to an increased risk of dementia. Although there are anecdotal reports or observational studies suggesting an association between PPIs and cognitive decline, controlled clinical trials designed to investigate this link have generally not shown a clear causal relationship between PPI use and dementia.

It is also important to understand that dementia is a complex condition with multifactorial causes, including genetic predisposition, age-related changes, and various environmental factors. Remember that many patients who take PPIs may also have other risk factors for dementia unrelated to their medication use. Several studies suggesting a link between PPIs and dementia have been criticized for not adequately accounting for other factors (including the study by Northuis et al reviewed in the next summary) that could contribute to cognitive decline, such as pre-existing health conditions, lifestyle factors, and the use of other medications.

Note to readers: At the time we reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.


Mehta RS, Kochar B, Zhou Z, et al. Association of proton pump inhibitor use with incident dementia and cognitive decline in older adults: a prospective cohort study. Gastroenterology 2023;165:564-572. (https://doi.org/10.1053/j.gastro.2023.05.052)

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