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PPIs Linked to Lower Cognitive Decline in Latest Study

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Sue Hughes

A new study has smoothed the waters somewhat over concerns about a possible increased risk for dementia with proton-pump inhibitors (PPIs).

In this latest observational, longitudinal study, individuals without dementia at baseline who were taking PPIs had a lower risk for cognitive decline than those were not taking PPIs.

In addition, both consistent and intermittent use of PPIs was associated with lower risk for cognitive decline with a suspected Alzheimer’s cause, and the same finding of a lower risk for cognitive decline in those taking PPIs was observed for individuals with normal cognition or mild cognitive impairment at baseline.

“The current findings do not support that PPIs are associated with greater risk of dementia despite mechanisms proposed as to why they should be,” lead author, Felicia C. Goldstein, PhD, Emory University, Atlanta, Georgia, and colleagues conclude.

Proposed mechanisms include PPIs being associated with higher β-amyloid levels in a mouse model and an association between use of PPIs and vitamin B12 deficiency. In addition, certain PPIs, including lansoprazole and omeprazole, cross the blood–brain barrier, demonstrating that they directly affect the brain.

“Caution needs to be exercised when speculating about the effect of PPIs on brain functioning until a randomized, prospective clinical trial elucidates the effect of PPIs on cognition,” the authors write.
The findings were published online in the Journal of the American Geriatrics Society on June 7.

“In contrast to recent reports which suggested a link between PPIs and dementia, this well-designed study adjusts for stratification bias risks and showed that there was no association of PPIs with dementia and specifically Alzheimer’s disease,” said David A. Johnson, MD, chief of gastroenterology at Eastern Virginia Medical School Norfolk, who was not involved in the research.

“Although prospective studies are needed to confirm these findings, these results should be helpful in guiding clinicians in discussions with their patients,” he told Medscape Medical News.

The current study included 10,486 individuals aged 50 years or older with a baseline diagnosis of normal cognition or mild cognitive impairment enrolled in the National Institutes of Health (NIH)–supported Alzheimer’s Disease Centers, a nationwide consortium of research sites in the United States. Participants underwent detailed annual neuropsychological evaluations.

With regard to PPI use, 884 individuals were taking PPIs at every visit, 1925 reported taking PPIs intermittently, and 7677 never reported taking PPIs.

Multivariable Cox regression analyses was used to evaluate the association between PPI use and annual conversion of baseline normal cognition to mild cognitive impairment or dementia, or annual conversion of baseline mild cognitive impairment to dementia, controlling for demographic characteristics, vascular comorbidities, mood, and use of anticholinergics and histamine-2 (H2) receptor antagonists.

Results showed that continuous (always vs never) PPI use was associated with lower risk for decline in cognitive function (hazard ratio [HR], 0.78; P = .005) and lower risk for conversion to mild cognitive impairment or Alzheimer’s disease (HR, 0.82; P = .03).

Intermittent use was also associated with lower risk for decline in cognitive function (HR, 0.84; P = .001) and risk for conversion to mild cognitive impairment or Alzheimer’s disease (HR, 0.82; P = .001). This lower risk was found for persons with normal cognition or MCI.

The authors note that another recent study (Int Psychogeriatr. 2016;28:1059-1065) found no link between PPI and dementia but two others (Eur Arch Psychiatry Clin Neurosci. 2015;265:419-428; JAMA Neurol. 2016;73:410-416) suggested a detrimental effect of PPIs.

They point out that a strength of the current study was the well-phenotyped sample of individuals; the study relied on diagnoses of cognitive status by a team of experienced clinicians in academic medical centers. In contrast, two of the previous investigations linking PPI use to dementia were conducted in individuals in primary care and relied on administrative databases using the diagnoses of a diverse group of practitioners, presumably with varying degrees of experience in diagnosing dementia, they write.

They further note that the current study included a broad age range of individuals, whereas prior studies were limited to persons in their mid-70s.

They also emphasize the importance of controlling for H2 antagonist use (not done in prior studies) because these drugs — also used to treat gastrointestinal disorders — have also been linked to increased risk for cognitive impairment. In fact, the current study found that H2 antagonist use decreased the risk for cognitive decline.

Dr Johnson elaborated on some of these issues for Medscape Medical News.

“The challenge in evaluating the evidence stems from the authors’ adjusting for some, but not all, of the confounding variables. In particular, the two prior studies which alleged dementia associated with PPI use did not include alcohol use, family history of dementia, and hypertension, which are well-known, significant risk factors for demen­tia. Therefore, potential major risk adjustments that may confound the findings were not reported,” he said.

“The present study by Goldstein et al assessed the conversion from normal cognitive function assessed by validated testing instruments — this separates the study from the other two retrospective studies alleging PPI related dementia,” he added. “The study uses appropriate risk adjustment for dementia and also adjusts for dose exposure to PPIs.”

The current study was funded by the Emory Alzheimer’s Disease Research Center. The authors have disclosed no relevant financial relationships. Dr Anderson has served as a director, officer, partner, employee, advisor, consultant, or trustee for Pfizer Inc, Epigenomics, WebMD, CRH Medical, and Medtronic.

J Am Ger Soc. Published online June 7, 2017. Abstract
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Medscape Medical News © 2017
Cite this article: PPIs Linked to Lower Cognitive Decline in Latest Study – Medscape – Jun 22, 2017.

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