Association of Proton Pump Inhibitor Use With Incident Dementia and Cognitive Decline in Older Adults: A Prospective Cohort Study

Abstract

Background & 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. We investigated the associations of PPI and histamine-2 receptor antagonist (H2RA) use with dementia and cognitive decline.

Methods: We 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, Fourth Edition, criteria. Secondary endpoints 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 vs nonuse was not associated with incident dementia (multivariable hazard ratio, 0.88; 95% confidence interval, 0.72-1.08), CIND (multivariable hazard ratio, 1.00; 95% confidence interval, 0.92-1.09), or with changes in overall cognitive test scores over time (multivariable B, -0.002; standard error, 0.01; P = .85). Similarly, no associations were observed between H2RA use and all cognitive endpoints.

Conclusions: In adults ≥65 years of age, PPI and H2RA use were not associated with incident dementia, CIND, or decline in cognition over time. These data provide reassurance about the safety of long-term use of PPIs among older adults.

Keywords: Cognition; Dementia; Pharmacoepidemiology; Proton Pump Inhibitors.

Figure 1.. Co-occurrence network analysis reveals patterns of medications concomitantly prescribed with PPIs in ASPREE.

Shown graphically are pairwise co-occurrences between all medications taken by ASPREE participants. Apart from PPIs (central yellow node), drugs were binned into groups (orange nodes), defined according to the World Health Organization Anatomical Therapeutic Chemical Classification System. Edges between nodes are shown given a minimum of 100 co-occurrences; as a result, singletons represent drug classes with fewer than 100 co-occurrences with other drugs. Connections to PPIs are emphasized in black and weighted according to the number of co-occurrences (strong, >750; moderate, >250; weak, >100).