Is omeprazole (proton pump inhibitor) linked to dementia?

Is Omeprazole Linked to Dementia?

The evidence regarding omeprazole and dementia risk is conflicting, but the most recent and highest-quality prospective study with rigorous methodology found no association between PPI use and dementia, providing reassurance about long-term safety in older adults. 1

Evidence Quality and Contradictions

The literature presents two opposing narratives that must be carefully weighed:

Studies Suggesting Increased Risk

• Observational claims-based studies from Germany found associations between PPI use and dementia, with hazard ratios ranging from 1.04 for PPI initiation to 1.85 for time-varying use versus non-use 2
• An earlier 2016 German study reported a 44% increased risk (HR 1.44,95% CI 1.36-1.52) in elderly patients receiving regular PPI medication 3
• A 2024 Danish nationwide study showed age-dependent associations, with incidence rate ratios of 1.36 for ages 60-69 years, declining to 1.03 for ages 90+ years 4
• A neuropsychological assessment study demonstrated impairments in verbal fluency, short-term episodic memory, selective attention, and executive functions with long-term omeprazole treatment 5

The Strongest Contradictory Evidence

The 2023 ASPREE post-hoc analysis represents the highest quality evidence available because it:

• Prospectively followed 18,934 community-based adults ≥65 years with rigorous in-person medication verification 1
• Used DSM-IV criteria for dementia diagnosis rather than claims-based coding, eliminating misclassification bias 1
• Found no association between baseline PPI use and incident dementia (multivariable HR 0.88,95% CI 0.72-1.08), cognitive impairment without dementia (HR 1.00,95% CI 0.92-1.09), or decline in cognitive test scores over time 1

Critical Methodological Differences

The key distinction lies in study design:

• Claims-based observational studies are vulnerable to confounding by indication (patients requiring PPIs may have underlying conditions associated with dementia risk), misclassification of dementia diagnosis, and incomplete medication histories 1
• The ASPREE trial addressed these limitations through prospective design, direct medication assessment, and standardized cognitive testing 1

Clinical Implications

For patients with definitive indications for PPI therapy (Barrett's esophagus, severe erosive esophagitis, high-risk NSAID users requiring gastroprotection, secondary prevention of gastric/duodenal ulcers), dementia concerns should not prompt discontinuation 6

For patients without clear ongoing indication, consider trial of de-prescribing based on general principles of medication optimization in older adults, not specifically due to dementia risk 6

Important Caveats

• The American Heart Association notes that observational data suggest long-term PPI use may be associated with increased cardiovascular risk independent of any dementia concerns, with 29% greater absolute risk of ischemic stroke and 36% greater risk of MI within 6 months compared to nonusers 7
• All PPI agents (omeprazole, pantoprazole, lansoprazole, esomeprazole) showed similar patterns in studies reporting associations, suggesting this is not specific to omeprazole 2
• The magnitude of any potential association appears to decrease with older age at diagnosis, with no association observed after age 90 years 4