Is there a link between proton pump inhibitor (PPI) use and Alzheimer's disease?

No Established Link Between PPI Use and Alzheimer's Disease

Based on current evidence, there is no established causal relationship between proton pump inhibitor (PPI) use and Alzheimer's disease or dementia. 1

Current Evidence on PPIs and Dementia

Evidence Against a Link

• The most recent and highest quality systematic review and meta-analysis of observational studies found no evidence to support an association between PPI use and increased risk of dementia, with a pooled hazard ratio of 1.10 (0.88-1.37) for all causes of dementia 1
• For Alzheimer's disease specifically, the pooled odds ratio was 0.96 (0.82-1.11), suggesting no increased risk 1
• A longitudinal observational study actually found that continuous PPI use was associated with lower risk of decline in cognitive function (HR = 0.78) and lower risk of conversion to mild cognitive impairment or Alzheimer's disease (HR = 0.82) 2

Evidence Suggesting a Possible Link

• A 2024 nationwide Danish population-based study reported an association between PPI use and dementia, with the strongest association in younger patients (age 60-69) with an incidence rate ratio of 1.36 (95% CI, 1.29 to 1.43) 3
• The association appeared to strengthen with longer treatment duration but weakened with older age at diagnosis 3

Clinical Implications for PPI Use

Appropriate PPI Prescribing

• The American Gastroenterological Association (AGA) recommends that all patients taking a PPI should have regular review of ongoing indications for use and documentation of that indication 4
• Primary care providers should be primarily responsible for reviewing the presence of ongoing indications for PPI use and identifying candidates for de-prescribing 4
• PPIs should only be continued when there is a definitive indication for chronic use, such as Barrett's esophagus, severe erosive esophagitis, or gastroprotection in high-risk patients 4

De-prescribing Considerations

• The decision to discontinue PPIs should be based solely on the lack of an indication for PPI use, and not because of concern for potential adverse events 4
• Patients without a definitive indication for chronic PPI use should be considered for trial of de-prescribing 4
• When de-prescribing PPIs, either dose tapering or abrupt discontinuation can be considered 4

Important Caveats and Pitfalls

• Most studies examining the relationship between PPIs and dementia are observational and subject to confounding factors 5
• The quality of evidence linking PPIs to dementia has been rated as "very low" using GRADE methodology 1
• Discontinuing PPIs in patients with definite indications based on concerns about unproven risks may lead to recurrent symptoms and serious complications 4
• Randomized controlled trials comparing PPIs with placebo have not shown a higher rate of adverse events among PPI users 4

Conclusion for Clinical Practice

When considering PPI therapy, clinicians should:

• Clearly document an acceptable indication for the drug and ensure the indication is ongoing 4
• Regularly review the need for continued therapy 4
• Consider step-down to once-daily dosing for patients on twice-daily regimens 4
• Not discontinue PPIs in patients with complicated GERD, Barrett's esophagus, or high risk for GI bleeding 4
• Not use concerns about dementia as a reason to discontinue PPIs when there is a valid indication for their use 4