From the AGA Journals

PPI use not linked to cognitive decline


Key clinical point: Use of proton pump inhibitors was not associated with cognitive decline.

Major finding: Mean baseline cognitive scores did not significantly differ between PPI users and nonusers, nor did changes in cognitive scores over time.

Study details: Two population-based studies of twins in Denmark.

Disclosures: Odense University Hospital provided partial funding. Dr. Wod had no disclosures. Three coinvestigators disclosed ties to AstraZeneca and Bayer AG.

Source: Wod M et al. Clin Gastro Hepatol. 2018 Feb 3. doi: 10.1016/j.cgh.2018.01.034.

Over the last 20 years, there have been multiple retrospective studies which have shown associations between the use of proton pump inhibitors (PPIs) and a wide constellation of serious medical complications. However, detecting an association between a drug and a complication does not necessarily indicate that the drug was indeed responsible.

Dr. Laura Towgarnik

The evidence supporting the assertion that PPIs cause cognitive decline is among the most tenuous of all the PPI/complication associations. The initial reports linking PPI use to dementia emerged in 2016 based on the results of a German retrospective analysis, which showed an association between PPIs and having a health care contact coded as dementia. However, this study had numerous methodological flaws, including the investigators not using a validated definition for dementia and not being able to control for conditions that may be more common in both PPI users and persons with dementia. In addition, there is little reason to believe that PPIs, based on their mechanism of action, should have any negative effect on cognitive function. Nevertheless, this paper was extensively cited in the lay press, and likely led to the inappropriate discontinuation of PPI therapy among persons with ongoing indications, or in the failure to start PPI therapy in persons who would have derived benefit.

This well-done study by Wod et al, which shows no significant association between PPI use and decreased cognition and cognitive decline will, I hope, serve to allay any misplaced concerns that may exist among clinicians and patients about PPI use in this population. This paper has notable strengths, most importantly having access to results of a direct, unbiased assessment of changes in cognitive function over time and accurate assessment of PPI exposure. Short of performing a controlled, prospective trial, we are unlikely to see better evidence indicating a lack of a causal relationship between PPI use and changes in cognitive function. This provides assurance that patients with indications for PPI use can continue to use them.

Laura E. Targownik, MD, MSHS, FRCPC, is section head, section of gastroenterology, University of Manitoba, Winnipeg, Canada; Gastroenterology and Endoscopy Site Lead, Health Sciences Centre, Winnipeg; associate director, University of Manitoba Inflammatory Bowel Disease Research Centre; associate professor, department of internal medicine, section of gastroenterology, University of Manitoba. She has no conflicts of interest.



Use of proton pump inhibitors (PPIs) is not associated with cognitive decline in two prospective, population-based studies of identical twins published in the May issue of Clinical Gastroenterology and Hepatology.

“No stated differences in [mean cognitive] scores between PPI users and nonusers were significant,” wrote Mette Wod, PhD, of the University of Southern Denmark, Odense, with her associates.


Past research has yielded mixed findings about whether using PPIs affects the risk of dementia. Preclinical data suggest that exposure to these drugs affects amyloid levels in mice, but “the evidence is equivocal, [and] the results of epidemiologic studies [of humans] have also been inconclusive, with more recent studies pointing toward a null association,” the investigators wrote. Furthermore, there are only “scant” data on whether long-term PPI use affects cognitive function, they noted.

To help clarify the issue, they analyzed prospective data from two studies of twins in Denmark: the Study of Middle-Aged Danish Twins, in which individuals underwent a five-part cognitive battery at baseline and then 10 years later, and the Longitudinal Study of Aging Danish Twins, in which participants underwent the same test at baseline and 2 years later. The cognitive test assessed verbal fluency, forward and backward digit span, and immediate and delayed recall of a 12-item list. Using data from a national prescription registry, the investigators also estimated individuals’ PPI exposure starting 2 years before study enrollment.

In the study of middle-aged twins, participants who used high-dose PPIs before study enrollment had cognitive scores that were slightly lower at baseline, compared with PPI nonusers. Mean baseline scores were 43.1 (standard deviation, 13.1) and 46.8 (SD, 10.2), respectively. However, after researchers adjusted for numerous clinical and demographic variables, the between-group difference in baseline scores narrowed to just 0.69 (95% confidence interval, –4.98 to 3.61), which was not statistically significant.

The longitudinal study of older twins yielded similar results. Individuals who used high doses of PPIs had slightly higher adjusted mean baseline cognitive score than did nonusers, but the difference did not reach statistical significance (0.95; 95% CI, –1.88 to 3.79).

Furthermore, prospective assessments of cognitive decline found no evidence of an effect. In the longitudinal aging study, high-dose PPI users had slightly less cognitive decline (based on a smaller change in test scores over time) than did nonusers, but the adjusted difference in decline between groups was not significant (1.22 points; 95% CI, –3.73 to 1.29). In the middle-aged twin study, individuals with the highest levels of PPI exposure (at least 1,600 daily doses) had slightly less cognitive decline than did nonusers, with an adjusted difference of 0.94 points (95% CI, –1.63 to 3.50) between groups, but this did not reach statistical significance.

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