Do PPIs Cause Alzheimer's Disease?
No, current evidence does not support that PPIs cause Alzheimer's disease, and concerns about dementia should not be used as a reason to discontinue PPIs when there is a valid clinical indication. 1
Evidence Quality and Guideline Recommendations
The American Gastroenterological Association explicitly states that the decision to discontinue PPIs should be based solely on the lack of an indication for PPI use, and not because of concern for PPI-associated adverse events, including dementia 2, 1. This recommendation is grounded in the understanding that:
- No randomized controlled trials have demonstrated that PPI users have an increased incidence of dementia or other purported adverse events 2, 3
- The associations reported in observational studies can be explained by residual confounding and analytic biases 2
- Many proposed mechanisms lack biological plausibility in real-world clinical contexts 2
Conflicting Research Evidence
While guidelines are clear, the research literature shows contradictory findings:
Studies showing no association:
- A 2017 study using healthcare registry data found no association between PPI use and Alzheimer's dementia, with no increased risk even with long-term use or higher doses 4
- Discrepancies between studies likely relate to multiple testing and residual confounding, with insufficient evidence for causality 4
Studies suggesting possible association:
- A 2024 Danish nationwide cohort study of nearly 2 million individuals found increased dementia rates in PPI users, particularly in those diagnosed before age 90 (IRR 1.36 for ages 60-69, decreasing to 1.03 for ages 90+) 5
- A 2020 Spanish study found no increased risk of Alzheimer's specifically (OR 1.06), but a weak association with non-Alzheimer's dementias (OR 1.20) 6
Mechanistic hypotheses:
- Laboratory studies propose that PPIs might inhibit vacuolar proton pumps in microglial lysosomes, potentially impairing amyloid-beta clearance 7
- In vitro research suggests PPIs inhibit choline-acetyltransferase, the enzyme responsible for acetylcholine synthesis 8
Clinical Decision-Making Algorithm
When to CONTINUE PPIs despite dementia concerns:
- Barrett's esophagus (reduces esophageal adenocarcinoma risk) 3
- Severe erosive esophagitis (LA grade C/D) 3
- Gastroprotection in high-risk patients on NSAIDs/aspirin, anticoagulants, or multiple antithrombotics 2, 9
- History of upper GI bleeding or peptic ulcer disease 2, 9
- Age >60-65 years on chronic NSAIDs 9
- Concurrent corticosteroid use with antithrombotics 9
When to CONSIDER de-prescribing:
- No definitive ongoing indication documented 1, 9
- Low-risk patients without complicated GERD 9
- Patients on twice-daily dosing who could step down to once-daily 9, 3
De-prescribing approach when appropriate:
- Either abrupt discontinuation or gradual tapering are acceptable 2, 1
- Warn patients about rebound acid hypersecretion (RAHS) lasting 2-6 months 9, 3
- Offer on-demand PPIs, H2-receptor antagonists, or antacids for symptom management 2, 9
- Monitor for severe persistent symptoms beyond 2 months, which may indicate need to resume therapy 9
Critical Pitfalls to Avoid
Do not discontinue PPIs in patients with definitive indications based on unproven dementia concerns - this may lead to serious complications including recurrent ulcers, bleeding, or progression of Barrett's esophagus 1, 3. The documented benefits of PPIs in preventing GI bleeding and complications far outweigh theoretical dementia risks in appropriate patients 2.
Patient anxiety about PPI-related adverse effects is common, with nearly 40% attempting self-discontinuation without physician guidance 2. This underscores the need for clear communication that current evidence does not support causality, and that discontinuation decisions should be based on indication review, not fear of adverse events 2, 1.