New PPI Data Again Link Medication Use to Alzheimer's

Abdullah Hashmi, MD

April 01, 2022

The study covered in this summary was published in and has not yet been peer reviewed.

This case–control study provided supportive evidence that previous proton pump inhibitor (PPI) use might increase the risk for Alzheimer's disease, regardless of current or past use or duration of first- or second-generation PPIs.

Key Takeaways

  • This nested case–control study of the Korean population showed that the development of Alzheimer's disease in people older than 60 years was more likely with PPI use.

  • This increase in the risk for Alzheimer's disease with PPI use was maintained regardless of age, sex, income, region of residence, smoking, alcohol consumption, blood pressure, fasting blood glucose, total cholesterol, or gastroesophageal reflux disease status.

Why This Matters

  • The burden of Alzheimer's disease on public health is growing as the population ages. In elderly people, it is important to study the neurologic adverse effects of commonly used medications for dementia prevention.

  • Conclusions about the association between PPI use and dementia have been conflicting. This study was designed specifically to focus on the impact of PPIs on Alzheimer's risk.

  • The findings provide supportive evidence regarding previous pharmacoepidemiologic studies, and encourage cautious and strict application of PPI medication (one of the most commonly used medications worldwide) to prevent the development of Alzheimer's disease.

Study Design

  • A retrospective cohort study with a nested case–control design was used to determine the effect of PPI on risk for the development of Alzheimer's disease.

  • The 17,225 patients with Alzheimer's disease identified in the Korean National Health Insurance Service–Health Screening Cohort (KNHIS-HSC) database were propensity matched, in a 1:4 ratio, with 68,900 control subjects on the basis of age, sex, income, and region of residence.

  • PPI prescription duration for the year prior to the diagnosis of Alzheimer's disease was retrospectively reviewed. Days of PPI use were defined as prescription days during the year before the index Alzheimer's disease diagnosis.

  • Patients were classified as nonusers, current PPI users (prescribed at least once in the previous 30 days), or past PPI users (prescribed at least once in the previous 31 to 365 days). Patients were further categorized by duration of exposure to PPIs as nonusers or users — for fewer than 30 days, for 30 to 90 days, or for more than 90 days — based on prescriptions in the year before the Alzheimer's diagnosis.

  • Patients younger than 60 years or any patients with missing records of body mass index (BMI), fasting blood glucose, or cholesterol were excluded from the analysis.

Key Results

  • Demographic characteristics (age group, sex, economic level) were matched exactly for the 17,225 Alzheimer's patients and the 68,900 control subjects (standardized difference, 0).

  • The odds of developing Alzheimer's disease were significantly higher in current (odds ratio [OR], 1.36; P < .001) and past (OR, 1.11; P < .001) PPI groups than in the control group.

  • Participants with PPI prescriptions for fewer than 30 days (OR, 1.13; P < .001), 30 to 90 days (OR, 1.18; P < .001), or more than 90 days (OR, 1.26; P < .001) all had higher odds of developing Alzheimer's disease than those in control group. An increased association between the cumulative duration of PPI exposure and the development of Alzheimer's disease was also observed. The odds of developing Alzheimer's disease were higher for users with more than 30 days of exposure than for those with fewer than 30 days.

  • The incidence of Alzheimer's disease was higher for patients exposed to first- or second-generation PPIs, regardless of duration of exposure. Specifically, for patients with exposure for fewer than 30 days, the odds ratios for first- and second-generation PPIs were 1.14 and 1.13, respectively; for patients with exposure for 30 to 90 days, the odds ratios were 1.19 and 1.17, respectively, and for patients with exposure for more than 90 days, the odds ratios were 1.18 and 1.27, respectively.


  • The length of time for previous PPI prescription — the 1-year period before Alzheimer's diagnosis — was short.

  • The actual medication intake by patients could not be monitored.

  • Because the study was retrospective, unmeasured confounding effects could not completely be excluded.

  • Family history of Alzheimer's disease and genetic information were unavailable in the health insurance data and therefore not taken into consideration.


  • The study received no commercial funding.

  • None of the authors disclosed relevant financial relationships.

This is a summary of a preprint research study, Associations between proton pump inhibitors and Alzheimer's disease: A nested case-control study using a Korean nationwide health screening cohort , written by researchers at the Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Gangwon, Republic of Korea, published on ResearchSquare, and provided to you by Medscape. This study has not yet been peer-reviewed. The full text of the study can be found on


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