Does chronic omeprazole use for gastro‑esophageal reflux disease in an elderly patient increase the risk of dementia?

Does Omeprazole Cause Dementia?

The evidence linking omeprazole and other proton pump inhibitors (PPIs) to dementia risk is observational and cannot establish causation, but the association is concerning enough to warrant careful consideration of necessity, duration, and alternatives when prescribing PPIs to elderly patients.

Evidence Summary

Observational Studies Show Association, Not Causation

The most recent and comprehensive evidence comes from a 2023 German claims database study of over 7.6 million individuals, which found:

• Time-varying PPI use versus non-use was associated with an 85% increased risk of dementia (HR 1.85,95% CI 1.80-1.90) 1
• PPI initiation versus non-initiation showed only a modest 4% increased risk (HR 1.04,95% CI 1.03-1.05), suggesting the association strengthens with ongoing use 1
• All PPI agents studied (omeprazole, pantoprazole, lansoprazole, esomeprazole) were associated with increased dementia risk 1

An earlier 2016 German study of 73,679 elderly patients (≥75 years) found regular PPI users had a 44% increased risk of incident dementia compared to non-users (HR 1.44,95% CI 1.36-1.52) 2

Important Limitations and Confounding

These observational studies cannot prove causation because:

• Confounding by indication: Patients requiring chronic PPI therapy may have underlying conditions (GERD, chronic inflammation, comorbidities) that independently increase dementia risk 3, 2
• The association may reflect reverse causation, where early cognitive changes lead to medication mismanagement or increased healthcare utilization 1
• No randomized controlled trials have examined dementia as an outcome with PPI use 4

Potential Biological Mechanisms

Laboratory and animal studies suggest plausible mechanisms, though clinical relevance remains uncertain:

• PPIs may modulate amyloid protein processing and increase β-amyloid levels in mouse brains 3, 2
• PPIs interfere with vitamin B12 absorption in a dose-dependent manner, and B12 deficiency can contribute to cognitive impairment 4
• Long-term PPI use (≥1 year) is associated with iron deficiency, which may affect cognition 4

Clinical Approach to PPI Use in Elderly Patients

When PPIs Are Indicated

For documented GERD or erosive esophagitis, omeprazole remains effective and appropriate therapy 5, 6:

• Omeprazole 20 mg daily maintains 82% of patients in endoscopic and symptomatic remission over 12 months 5
• Even 10 mg daily maintains remission in approximately one-third of patients with all grades of esophagitis 6

Minimize Unnecessary Exposure

Avoid empiric PPI therapy for hoarseness or laryngeal symptoms without documented GERD or esophagitis 4:

• Randomized trials show no benefit of esomeprazole 40 mg twice daily versus placebo for chronic laryngeal symptoms in patients without heartburn 4
• PPIs should not be prescribed empirically without clear indication 4

Regular Medication Review

The American Geriatrics Society recommends regular medication list review in patients with cognitive impairment, as medications can directly affect cognitive function 7:

• Re-evaluate cognitive function within 6 weeks after any medication adjustment 7
• Systematic medication review and deprescribing should precede extensive neurological workup 7

Use the Lowest Effective Dose

When PPIs are necessary:

• Start with the lowest effective dose (omeprazole 10-20 mg daily) 6
• Periodically attempt dose reduction or discontinuation to assess ongoing need 5, 6
• Consider on-demand or intermittent therapy rather than continuous use when appropriate 6

Key Pitfalls to Avoid

• Do not discontinue necessary PPI therapy based solely on observational dementia data—the association does not prove causation, and untreated GERD has its own morbidity 4, 5
• Do not ignore other PPI-related risks: PPIs increase risk of hip fractures (RR 1.20), hypomagnesemia (OR 1.71), vitamin B12 deficiency, and potentially community-acquired pneumonia 4
• Do not prescribe PPIs empirically for vague symptoms without documented acid-related disease 4
• Do not forget to screen for and correct vitamin B12 deficiency in patients on chronic PPI therapy, as this is a reversible cause of cognitive impairment 4, 7

Bottom Line

While observational data suggest an association between chronic PPI use and dementia risk, this does not establish causation. Prescribe PPIs only when clearly indicated, use the lowest effective dose, periodically reassess necessity, and maintain heightened awareness of this potential risk in elderly patients. When cognitive decline occurs in a patient on chronic PPI therapy, consider deprescribing as part of a systematic medication review, but balance this against the morbidity of untreated acid-related disease 7, 1.