Level 2 [mid-level] evidence

Proton pump inhibitors (PPIs) are commonly used to treat gastroesophageal reflux disease (GERD) and peptic ulcer disease. PPIs are widely available as both prescription and over-the-counter medications, and their use has been steadily increasing in certain populations, especially the elderly. However, a growing body of evidence has found an increased risk of adverse effects associated with use of PPIs, including bone fractures, cardiovascular events, acute nephritis and infection, and mortality. Recently, a large observational study from Germany examined whether long-term prescription PPI use was associated with an increased risk of dementia in the elderly. 1

Medical records of 73,679 persons aged 75 years or older without dementia were reviewed. Of these, 2,950 persons (4%) were taking regular PPI medication, defined as at least 1 PPI prescription in each quarter of an 18-month interval. The data was adjusted for confounding factors including age, sex, polypharmacy (≥5 prescription medications besides PPI), stroke, depression, ischemic heart disease, and diabetes. Overall, 40% of the study population developed dementia. Compared to no PPI use, regular PPI use was associated with an increased risk of incident dementia (adjusted hazard ratio, 1.44; 95% confidence interval [CI], 1.36-1.52). These results were consistent in subgroup analyses of women and men, and subgroup analyses by age found the risk of dementia with PPI use decreased with increasing age.

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The findings of this study suggest that regular PPI use by the elderly may be associated with an increased risk of dementia. This study agrees with previous findings from another German longitudinal study in elderly patients that found an increased risk of dementia with PPI use.2 

Several limitations should be considered when interpreting this study. First, it is not clear whether there were persons taking over-the-counter PPIs. Second, the APOE4 allele status and educational level of the persons in the study were not known, and these factors could also potentially influence the magnitude of risk. Finally, baseline rates of mild cognitive impairment, a major risk factor for dementia, were not assessed. While this study is not conclusive, it is one more reason to routinely review whether elderly patients taking PPIs need to continue them. Stopping unnecessary PPIs may save money and decrease harms. 

Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester. 

DynaMed is a database that provides evidence-based information on more than 3,000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals. 


  1. Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73[4]:410-416.
  2. Haenisch B, von Holt K, Wiese B, et al. Risk of dementia in elderly patients with the use of proton pump inhibitors. Eur Arch Psychiatry Clin Neurosci. 2015;265[5]:419-428.