Proton Pump Inhibitors and Risk of Mild Cognitive Impairment and Dementia

Felicia C. Goldstein, PhD; Kyle Steenland, PhD; Liping Zhao, MSPH; Whitney Wharton, PhD; Allan I. Levey, MD, PhD; Ihab Hajjar, MD, MS


J Am Geriatr Soc. 2017;65(9):1969-1974. 

In This Article

Abstract and Introduction


Objectives To examine the risk associated with the use of proton pump inhibitors (PPIs) of conversion to mild cognitive impairment (MCI), dementia, and specifically Alzheimer's disease (AD).

Design Observational, longitudinal study.

Setting Tertiary academic Alzheimer's Disease Centers funded by the National Institute on Aging.

Participants Research volunteers aged 50 and older with two to six annual visits; 884 were taking PPIs at every visit, 1,925 took PPIs intermittently, and 7,677 never reported taking PPIs. All had baseline normal cognition or MCI.

Measurements Multivariable Cox regression analyses evaluated the association between PPI use and annual conversion of baseline normal cognition to MCI or dementia or annual conversion of baseline MCI to dementia, controlling for demographic characteristics, vascular comorbidities, mood, and use of anticholinergics and histamine-2 receptor antagonists.

Results Continuous (always vs never) PPI use was associated with lower risk of decline in cognitive function (hazard ratio (HR) = 0.78, 95% confidence interval (CI) =0.66–0.93, P = .005) and lower risk of conversion to MCI or AD (HR = 0.82, 95% CI = 0.69–0.98, P = .03). Intermittent use was also associated with lower risk of decline in cognitive function (HR = 0.84, 95% CI = 0.76–0.93, P = .001) and risk of conversion to MCI or AD (HR = 0.82, 95% CI = 0.74–0.91, P = .001). This lower risk was found for persons with normal cognition or MCI.

Conclusion Proton pump inhibitors were not associated with greater risk of dementia or of AD, in contrast to recent reports. Study limitations include reliance on self-reported PPI use and lack of dispensing data. Prospective studies are needed to confirm these results to guide empirically based clinical treatment recommendations.


Proton pump inhibitors (PPIs) are a class of drugs prescribed to treat gastrointestinal disorders such as duodenal ulcers and gastroesophageal reflux disease by reducing gastric acid secretion. The safety of PPIs with respect to cognitive function, including the risk of dementia and Alzheimer's disease (AD), has recently been questioned. Two studies reported that PPIs were associated with greater risk of incident dementia and AD in persons aged 75 and older, raising concerns about their widespread use in older adults.[1,2] One investigation[1] included 3,076 persons (23% PPI users) enrolled in the multicenter German Study of Aging, Cognition and Dementia in Primary Care Patients. These community-residing individuals were aged 75 and older and were judged not to have dementia at baseline according to a battery of measures from the Structured Interview for Diagnosis of Dementia of Alzheimer type, Multi-infarct Dementia and Dementia of other Aetiology[3] consisting of the Mini-Mental State Examination, the activity of daily living scale, and the Hachinski-Rosen Scale. These measures were repeated at 18-month intervals. The investigators found a greater risk of dementia (hazard ratio (HR) = 1.38, 95% confidence interval (CI) = 1.04–1.83, P = .02) and AD (HR = 1.44, 95% CI = 1.01–2.06, P = .04) in PPI users than in nonusers over a follow-up period of 72 months. A subsequent study by the same investigators[2] used the claims data of the largest health insurance company in Germany. The inpatient and outpatient diagnoses of 73,679 individuals (4% PPI users) aged 75 and older with and without a dementia diagnosis at baseline over a 7-year period were examined. PPI users had a significantly greater risk of incident dementia than nonusers (HR = 1.44, 95% CI = 1.36–1.52, P < .001).

The finding of a 1.4 times greater risk of dementia with PPI use[1] would mean an increase of 10,000 more new cases of dementia each year in persons aged 75 to 84,[4] although a recent case–control study[5] on risk factors for dementia, also conducted in Germany, did not observe greater risk associated with PPI use. That study obtained general practitioner medical record information from a database of individuals aged 70 to 90 with (n = 11,956; 44.3% PPI users) or without (n = 11,956; 45.8% PPI users) a diagnosis of dementia over a 5-year period. The use of PPIs was associated with lower risk of developing dementia (HR = 0.93, 95% CI = 0.90–0.97).

Proton pump inhibitor use has risen in middle-aged and older adults in the United States, as reported in the National Health and Nutrition Examination Survey, in which the prevalence of prescription PPIs increased significantly from 4.9% to 8.3% in persons aged 40 to 64 from 1999 to 2012.[6] The authors of the current study therefore believed that it was important to investigate the association between PPI use and risk of mild cognitive impairment (MCI) and dementia. The sample included individuals enrolled in the National Institutes of Health (NIH), National Institute on Aging (NIA)–supported Alzheimer's Disease Centers (ADCs), a nationwide consortium of research sites in the United States. Subjects underwent detailed annual neuropsychological evaluations. The current study examined the risk of incident MCI, dementia, and specifically AD associated with PPI use during follow-up. The second aim was to examine in a subgroup of persons with MCI at baseline whether PPI use conferred a higher risk of dementia and AD conversion in an already vulnerable group than in persons with normal cognitive function at baseline. All analyses controlled for histamine-2 receptor antagonists (H2RAs) (cimetidine, ranitidine, famotidine, nizatidine) because these are an alternative treatment for gastric acid–related disorders. One study[7] found that use of H2RAs was a risk factor for incident cognitive impairment in a community-residing sample of African Americans aged 65 and older. In contrast, PPIs were not associated with greater risk. Because prior studies did not separately control for H2RA medications, it was important to determine whether they accounted for the conflicting findings.