Prolonged Proton Pump Inhibitor Usage Linked to Elevated Dementia Risk


Proton Pump Inhibitors (PPIs) are widely prescribed medications for acid-related digestive disorders such as Gastroesophageal Reflux Disease (GERD), peptic ulcers, and gastritis. These drugs work by reducing the production of stomach acid. While PPIs are generally considered safe and effective for short-term use, emerging research has raised concerns about their long-term consequences.1

The excessive use of PPIs poses a significant health issue, as these medications are associated with negative outcomes, including chronic kidney disease, heart problems, stroke, and dementia. One of the most concerning findings is the potential link between prolonged PPI usage and an elevated risk of dementia.1,2

While meta-analyses of cohort and case-control studies found no PPI-dementia link, these studies mainly involved Asian or white populations, limiting generalization. Additionally, diagnosing dementia with ICD codes lacks sensitivity.1

About the Study1

  • In this study, researchers delve into the link between new-onset dementia and present PPI usage and total PPI exposure, utilizing data from the Atherosclerosis Risk in Communities (ARIC) study. The ARIC research enlisted men and women of Black and White backgrounds aged 45 to 64 from four U.S. communities.
  • Information on typical PPI consumption came from the fifth ARIC study visit. As a result, this study marks Visit 5 as the starting point for analyzing PPI usage’s influence on new-onset dementia.
  • Comprehensive medication data, encompassing prescription and non-prescription drugs, was meticulously collected from all participants. This was thoroughly examined to gauge PPI usage. Additionally, annual phone call data was employed to ascertain chronic PPI use.
  • Present PPI usage was established based on reported PPI usage at Visit 5. At the same time, cumulative PPI exposure was calculated by considering the number of years of PPI usage registered from Visit 1 up to the 2011 annual phone call. Those who did not report PPI usage at Visit 5 were the reference group for comparison.
  • For comparison, the secondary analysis investigated Histamine2 Receptor Antagonists (H2RAs), an alternative treatment for conditions like GERD. In the secondary analysis, the team scrutinized (H2RAs) as an alternative treatment for GERD and other gastroesophageal issues.

Covariates and Adjustments

Dementia was evaluated through in-person neuropsychological tests, telephonic screenings, death records, and hospital discharge codes. A team of neuropsychologists and physicians confirmed suspected cases.

Race, age, gender, smoking habits, BMI, and medication usage factors were considered. Blood pressure and fasting blood glucose levels were assessed for hypertension and diabetes. Hazard ratios were adjusted for additional health conditions, medication use, and demographic factors.2

Extended Use of PPIs Associated with Increased Dementia Risk

Positive relationships were found between the use of PPIs and the risk of dementia; however, these associations were not statistically significant during a 5.5-year median follow-up period. Despite this, a study examining cumulative PPI usage and its relationship to incident dementia found a 33% higher risk of dementia in later life.1,2

Individuals who used PPIs for more than 4.4 years when middle aged have a considerably larger chance of having dementia later in life than those who did not use PPIs. The link between PPI usage and dementia has been explained by two putative mechanisms:

  • Impaired amyloid metabolism
  • Vitamin B12 insufficiency.2

The utilization of PPIs has been demonstrated to lower vitamin B12 levels, crucial for cognitive function. Nevertheless, in the current study, accounting for participants’ initial vitamin B12 supplementation did not alter the outcomes.3

Furthermore, mouse model research has revealed elevated β-amyloid levels in the brain following PPI administration. PPIs are thought to modify the γ-secretase enzyme, responsible for β-amyloid cleavage, potentially leading to the buildup of β-amyloid plaques in the brain.2,3

Clinical Considerations

It is essential to approach this association with caution. While the findings are concerning, they do not prove that PPIs directly cause dementia. Many factors may contribute to dementia, and the relationship between PPIs and this condition is likely complex.2

If an individual takes PPIs for an extended period, discussing the treatment plan with a healthcare professional is crucial. They can help assess the risks and benefits of continued PPI use, explore alternative treatments, or recommend lifestyle changes to manage acid-related issues. Moreover, regular monitoring of cognitive function and vitamin B12 levels may be advisable for those on long-term PPI therapy.3


Researchers find a positive connection between long-term PPI use and the risk of developing dementia, and it’s important to emphasize that there is no significant association between using PPIs at the present moment and an increased risk of dementia. It is a topic that warrants further research and consideration. While PPIs effectively manage acid-related disorders, they should be used judiciously, especially over extended periods. Individuals who require long-term PPI therapy should work closely with their healthcare providers to weigh the risks and explore alternatives, all while staying informed about the latest developments in this area of medical research. Proactively communication between patients and healthcare professionals is key to ensuring the safest and most appropriate treatment strategies.


  1. Long-term use of proton pump inhibitors associated with increased risk of dementia. (Accessed 06 Sep 2023). Available at: utm_source=news_medical_newsletter&utm_medium=email&utm_campaign=alzheimer_s_disease_newsletter_21_august_2023
  2. Northuis, C., Bell, E., Lutsey, P., et al; Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study. Neurology. 2023.  DOI:10.1212/WNL.0000000000207747
  3. Gomm W, von Holt K, Thome F, et al; Association of Proton Pump Inhibitors with Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis. JAMA Neurology. 2016;73(4):410–416.  doi:10.1001/jamaneurol.2015.4791
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