Does PPI Use Increase Risk for Dementia?

Summary and Comment |
February 24, 2016

Does PPI Use Increase Risk for Dementia?

  1. David A. Johnson, MD

A positive association should be interpreted with caution.

  1. David A. Johnson, MD

A few previous studies show a link between use of proton-pump inhibitors (PPIs) and cognitive decline or dementia. Findings of mouse models in which the use of PPIs increased the levels of β-amyloid in the brain are suggestive of a causal relation. Elevated prevalence of these amyloid plaques are reported in patients with Alzheimer's dementia.

In a prospective cohort study, researchers investigated the association between the use of PPIs (omeprazole, pantoprazole, lansoprazole, esomeprazole, or rabeprazole) and risk for dementia using insurance claims data (inpatient and outpatient diagnoses and drug prescriptions; 2004 to 2011) from 73,679 German patients aged ≥75 years. They used time-dependent Cox regression modeling, incorporating potential confounding factors of age, sex, comorbidities (depression, stroke, diabetes, ischemic cardiac disease), and polypharmacy.

Overall, patients receiving regular PPIs were significantly more likely to develop incident dementia compared with those not taking PPIs (hazard ratio, 1.44).


These findings need to be interpreted with caution. First, this study lacks adjustment for well-recognized risk factors for dementia, particularly family history, heavy alcohol use, hypertension, and atherosclerosis. Second, the proposed mechanism of harm for PPIs is elevation of β-amyloid, which has been independently associated with Alzheimer dementia, yet only 2.5% of patients had this diagnosis. Further limitations include the use of diagnostic codes rather than validated instruments to establish the diagnosis of dementia and lack of adjustment for use of over-the-counter histamine-2 receptor antagonists (linked to similar dementia risk in prior reports) or PPIs, both available in Germany beginning in 2003 and 2009, respectively.

Editor Disclosures at Time of Publication

  • Disclosures for David A. Johnson, MD at time of publication Consultant / Advisory board Medscape; Pfizer; CRH Medical Corporation; Covidien; Janssen; American Board of Internal Medicine; American College of Gastroenterology; WebMD Equity CRH Medical Corporation; Bovie Medical Corporation Editorial boards ACG Education Universe; Medscape Gastroenterology Leadership positions in professional societies American Board of Internal Medicine (Gastroenterology Examination Board); ACG Education Universe (Co-editor)


Reader Comments (5)


This kind of poor "evidence" is causing some poorly informed doctors to stop all PPI use in their elderly patients !

Jones, MD, Michael Physician, Internal Medicine, Houston, Texas

Dear Susan Linke, the "link" between B12 absorption and PPI use was debunked several decades ago, as was the supposed link between PPIs and osteopenia (see Targownik, Am J Gastro 2012 or 2013). The point of these articles is to bring you up to speed, not really dig up confusion from the distant past.

patrizia gambino Medical Student, Other

l'uso di PPI disturba la digestione e comporta cibo indigerito nel'intestino con rischio di danno alla barriera intestinale e possibile traslocazione di batteri, comunque i cibo non digerito nell'lume intestinale stimola il sistema immune

victor kantariya Physician, Family Medicine/General Practice

Effect of PPI Therapy on vitamin B12,vitamin D, and Iron Levels?Vitamin D,and Vitamin B12 deficiency and iron malabsorption has never been demonstrated in patients taking PPIs(Aliment Pharmacol Ther 2015) . Long-term safety of PPI therapy remains unclear. Victor Kantariya, MD

Susan Linke MBA MS RD LD Other Healthcare Professional, Allergy/Immunology, Dallas, TX Private Practice

PPIs are associated with a reduction in B12 and other vitamins and minerals, so the association with dementia could be tied to this.

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