Esophagus to Small Intestine

Gastroenterology. 2023;165(3):564–72.e1

Mehta RS, Kochar B, Zhou Z, Broder JC, Chung P, Yang K, Lockery J, Fravel M, Ryan J, Mahady S, Orchard SG, McNeil JJ, Murray A, Woods RL, Ernst ME, Chan AT

Association of proton-pump inhibitor use with incident dementia and cognitive decline in older adults: A prospective cohort study

Background and aims: Prior studies have suggested that proton-pump inhibitor (PPI) use is associated with increased risk of dementia; however, these have been limited by incomplete assessment of medication use and failure to account for confounders. Furthermore, prior studies have relied on claims-based diagnoses for dementia, which can lead to misclassification. The associations of PPI and histamine-2 receptor antagonist (H2RA) use with dementia and cognitive decline were investigated.
Methods: The authors conducted a post-hoc analysis of ASPirin in Reducing Events in the Elderly (ASPREE), a randomized trial of aspirin in the United States and Australia, including 18,934 community-based adults ≥ 65 years of all races/ethnicities. Baseline and recent PPI and H2RA use were determined according to review of medications during annual in-person study visits. Incident dementia was defined according to Diagnostic and Statistical Manual for Mental Disorders, 4th Edition, criteria. Secondary end points include cognitive impairment, no dementia (CIND) and changes in cognition. Associations of medication use with dementia and CIND outcomes were examined using Cox proportional hazards models. Changes in cognitive test scores were examined using linear mixed-effects models.
Results: Baseline PPI use versus non-use was not associated with 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 with changes in overall cognitive test scores over time (multivariable B, -0.002; standard error, 0.01; p = 0.85). Similarly, no associations were observed between H2RA use and all cognitive end points.

Conclusions: In adults ≥ 65 years of age, proton-pump inhibitor (PPI) and histamine-2 receptor antagonist use were not associated with incident dementia, cognitive impairment, no dementia, or decline in cognition over time. These data provide reassurance about the safety of long-term use of PPIs among older adults.

A.T. Chan, M.D., Gastroenterology Unit, Harvard Medical School/Massachusetts General Hospital, Boston, MA, USA, E-Mail:

DOI: 10.1053/j.gastro.2023.05.052

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