PPI Use and Dementia Development: Is There a Link?

PPIs are frequently used off-label and are easily accessible as over-the-counter products, contributing to the potential for adverse events or drug-drug interactions.

Over the last several years, proton pump inhibitors (PPIs) have come under increased scrutiny based on their potential for adverse events, especially in the settings of off-label use or excessive duration of therapy. As a result, up to 50% of patients undergoing treatment with PPIs may be doing so for an inappropriate indication.1 This can be an especially challenging issue among elderly patients, of whom 15% to 18% use PPIs.2 PPIs can frequently be added to an elderly patient’s medication regimen when they are admitted to a hospital and not discontinued on follow-up visits. They are also regularly prescribed by primary care physicians and a multitude of specialists, including gastroenterologists, pulmonologists, and otolaryngologists. Additionally, patients do not require a prescription to obtain numerous PPIs as they are often available as over-the-counter products.3 

Adverse events that have been reported in patients undergoing treatment with PPIs include cardiovascular disease, chronic kidney disease, increased risk for infection including pneumonia and Clostridioides difficile, and dementia.3,4 Although the exact underlying pathophysiology contributing to a potential link between PPIs and dementia is not known, it is possible that PPIs may lead to increased deposition of amyloid beta peptides in the brain, while also predisposing patients to vitamin B12 deficiency.4,5 

Both patients and their caregivers have become increasingly aware of the potential risks associated with PPI treatment, with dementia in particular being a very common concern voiced to physicians. To further clarify the potential association between PPIs and dementia, Muhammad Ali Khan, MD, of the Division of Gastroenterology and Hepatology at the University of Alabama in Birmingham, and colleagues conducted a systematic review and meta-analysis, the results of which have been published in the American Journal of Gastroenterology.5

The authors identified 11 observational studies that met inclusion criteria. A total of 642,949 patients were included in these studies (64% women), of whom 158,954 (24.7%) received underwent treatment with PPIs (483,995 non-PPI users [75.2%]). Most studies included patients who had been undergoing treatment with PPIs for 5 to 10 years. Ten studies were considered of high quality, while the remaining study was of moderate quality. 

The pooled hazard ratio (HR) for dementia was 1.10 (95% CI, 0.88-1.37). When Alzheimer dementia alone was evaluated, the HR was 1.06 (95% CI, 0.72-1.55). Similarly, the pooled odds ratio (OR) was 1.03 (95% CI, 0.84-1.25) for all causes of dementia and 0.96 (95% CI, 0.82-1.11) for Alzheimer dementia.  

These findings contrast with those of a 2015 study4 reporting that patients who underwent treatment with PPIs were found to have a significantly increased risk of any form of dementia (HR 1.38 [95% CI, 1.04-1.83] and Alzheimer dementia (HR 1.44 [95% CI, 1.01-2.06]) compared with patients not receiving PPIs.

Dr Khan and colleagues found no evidence to support an association between PPI use and increased risk of dementia.5 When considering the results of this study, it is important to note that this was a meta-analysis and systematic review; therefore, it can be challenging to accurately measure the impact of PPIs on dementia risk based on the lag-time for dementia to develop in patients. As most of the studies evaluated patients for a duration of between 5 and 10 years, longer-term follow-up data are lacking. Conducting a prospective, long-term study will be challenging to complete based on potential ethical and logistical concerns. Finally, the investigators noted challenges in tracking the dosing and duration of PPIs in all studies, which may have affected the results. 

Although Dr Khan and colleagues5 found no association between PPIs and dementia, it remains critical to perform a thorough medication reconciliation of all patients undergoing treatment with PPIs to determine if they are receiving them appropriately. Appropriate uses for PPIs include treatment of gastroesophageal reflux disease and peptic ulcer disease (including nonsteroidal anti-inflammatory drug-induced ulcers); prevention of nonsteroidal anti-inflammatory drug-induced ulcers, Barrett’s esophagus, and hypersecretory states such as Zollinger-Ellison syndrome; and eradication of Helicobacter pylori infection.6

The lowest effective dose of a PPI should be used. It is prudent to have a detailed discussion with patients regarding the potential risks associated with treatment and to add corresponding documentation of the discussion to their electronic health record. The potential adverse events associated with PPIs will continue to be a highly debated and researched topic, and when reviewing studies evaluating these links, it is important to note that association is different than causation.

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1. Heidelbaugh JJ, Goldberg KL, Inadomi JM. Magnitude and economic effect of overuse of antisecretory therapy in the ambulatory care setting. Am J Manag Care. 2010;16(9):e228-234.  

2. Qato DM, Wilder J, Schumm LP, Gillet V, Alexander GC. Changes in prescription and over-the-counter medication and dietary supplement use among older adults in the United States, 2005 vs 2011. JAMA Intern Med. 2016;176(4):473-482.  

3. Vaezi MF, Yang YX, Howden CW. Complications of proton pump inhibitor therapy. Gastroenterology. 2017;153(1):35-48.

4. 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.  

5. Kahn, MA, Yuan Y, Iqbal U, et al. No association linking short-term proton pump inhibitor use to dementia: Systematic review and meta-analysis of observational studies. Am J Gastroenterol. 2020;115(5):671-678.

6. Protonix. Prescribing information. Pfizer; 2018. Accessed July 21, 2020.