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PPI, H2RA Use by Older Adults Not Associated With Dementia or Cognitive Impairment

Key findings

  • Influenced by media reports, many older adults are apprehensive about using proton pump inhibitors (PPIs), but most previous studies of their link to dementia had serious methodologic limitations
  • This study of 18,934 older adults was a post hoc analysis of a prospective trial that included annual face-to-face visits and frequent, detailed cognitive testing adjudicated by an expert panel
  • Baseline, new and ongoing use of a PPI or histamine-2 receptor antagonist was not associated with risk of dementia, cognitive impairment or overall cognitive decline over more than six years of follow-up
  • Given the rigor of this study design, prescribers can reassure older adults using PPIs that reports about an association between longer-term PPI use and dementia are unlikely to be true

In 2016, a retrospective analysis of a large German administrative claims database, published in JAMA Neurology, concluded patients prescribed proton pump inhibitors (PPIs) had a nearly 1.5-fold increased risk of incident dementia diagnosis compared with those not prescribed PPIs. Subsequent observational studies and meta-analyses found conflicting results, but there has been widespread attention to this risk in the lay press.

Most research to date, including the German study, had methodologic limitations: incomplete assessment of the use of PPIs, which are often available over the counter; failure to account for important confounders, including the use of other medications; and reliance on diagnosis codes for dementia, which can lead to differential misclassification and thus overestimate effect size.

Researchers at Massachusetts General Hospital conducted a much more rigorous analysis, a post hoc analysis of the ASPirin in Reducing Events in the Elderly (ASPREE) trial. In Gastroenterology, they report that among adults ≥65 years of age, the use of PPIs or histamine-2 receptor antagonists (H2RA) was not associated with incident dementia, cognitive impairment or even decline in cognition over time.

The authors are Raaj S. Mehta, MD, MPH, researcher in the Division of Gastroenterology at Mass General, and instructor in Medicine at Harvard Medical School; Bharati Kochar, MD, MSCR, a gastroenterologist in the Division and assistant professor in Medicine at Harvard Medical School, Andrew T. Chan, MD, MPH, chief of the Clinical and Translational Epidemiology Unit, vice chief for clinical research in the Division at Mass General, and director of Cancer Epidemiology at the Mass General Cancer Center, and the Daniel K. Podolsky professor of Medicine at Harvard Medical School; and colleagues.


ASPREE was a randomized controlled trial that compared daily low-dose aspirin and placebo in Australian adults ages 70 and older and U.S. adults ages 65 and older. Enrollment occurred between 2010 and 2014. All participants were free of cardiovascular disease, dementia, and independence-limiting physical disability at trial entry and were expected to survive at least five years.

Participants underwent annual face-to-face visits, with detailed cognitive testing at baseline, years 1, 3, and 5, and the final visit in 2017. Cognitive testing results were adjudicated by an expert panel using validated criteria. The median follow-up was 4.5 years. After the trial ended, participants were invited to participate in the ASPREE-eXTension study (ASPREE XT), which is ongoing and involves annual cognitive testing.

The current analysis included 18,934 participants in ASPREE and ASPREE XT who were followed for up to seven years. At enrollment in ASPREE, 25% used a PPI and 1.9% used an H2RA.

Compared with nonusers, PPI users took more medications at baseline, most commonly antihypertensives, analgesics, and lipid-modifying agents.


Analyses were adjusted for age, sex, years of education, country, race/ethnicity, smoking status, alcohol consumption, body mass index, family history of dementia, chronic kidney disease, type 2 diabetes, hypertension, depression score, baseline cognition, the randomized trial intervention (aspirin or placebo) and the drug class most commonly used concurrently.

In ASPREE, no significant association was found between baseline, new or ongoing use of PPI or H2RA and:

  • Risk of probable Alzheimer's disease or other forms of dementia (primary outcome)
  • Risk of cognitive impairment without dementia
  • Overall cognitive test score at baseline
  • Change in overall cognitive test score over time

Likewise, in ASPREE XT there was no association between baseline PPI use and dementia. In ASPREE there was no evidence that any preselected dementia risk factor modified the association between PPI and risk of dementia.

Counseling Patients

This is the first study to combine rigorous ascertainment of dementia status with a prospective in-person collection of medication data and face-to-face cognitive assessments. Prescribers can use these data to reassure older adults using PPIs that media reports on the association between longer-term PPI use and dementia are unlikely to be true.

Prior links between PPIs and dementia might reflect PPI use as a marker of polypharmacy and comorbidity. Given the frequency with which PPIs were combined with anti-hypertensive agents and lipid-lowering agents in this cohort, PPI use could be a surrogate for cardiovascular disease, which is well known to be linked to adverse cognitive outcomes.

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