Long-term use of proton pump inhibitors associated with increased risk of dementia

In a recent study published in Neurology, researchers determine whether the current and cumulative use of prescription proton pump inhibitors (PPIs) increases the risk of incident dementia.

Study: Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study. Image Credit: Sonis Photography / Shutterstock.com


PPIs are commonly prescribed to provide short-term relief for peptic ulcers and gastroesophageal reflux disease (GERD). Over the past decade, the use of PPIs has significantly increased, with over half of PPI prescriptions not linked to a documented diagnosis of a gastrointestinal problem.

The rampant use of PPIs is a serious health concern, as these drugs have been linked to adverse effects such as chronic kidney disease, cardiovascular disease, stroke, and dementia. However, studies documenting the association between the use of PPIs and dementia have produced mixed results.

Although meta-analyses of cohort and case-control studies have reported no association between the use of PPIs and dementia, these studies have focused largely on Asian or white populations, thus making the results non-generalizable. Furthermore, the diagnosis of dementia using the International Statistical Classification of Diseases and Related Health Problems (ICD) codes is not sensitive.

About the study

In the present study, researchers examine the association between incident dementia and both current use and cumulative exposure to PPIs using the Atherosclerosis Risk in Communities (ARIC) study. The ARIC study recruited Black and White men and women between the ages of 45 and 64 years from four communities in the United States.

Data collected from the fifth visit of the ARIC study reported common PPI use. Therefore, the present study used Visit 5 as the baseline for assessing PPI use and its impact on incident dementia.

Information on all prescription and over-the-counter medications was gathered from all participants and inventoried to assess PPI use. Information gathered through annual phone calls was also used to determine chronic PPI use.

The current use of PPIs was defined based on the use of PPIs reported at Visit 5, whereas cumulative PPI exposure was determined based on the number of years of PPI use reported from Visit 1 to the 2011 annual phone call. Those who reported not using PPIs at Visit 5 were considered the reference group.

Histamine2 receptor antagonists (H2RAs), which are an alternative treatment option for GERD and other gastroesophageal problems, were examined as a comparator in the secondary analysis.

Dementia was assessed using neuropsychological examinations during in-person visits, screening tools completed during bi-annual telephonic follow-ups, death records, and hospital discharge codes. A panel of neuropsychologists and physicians confirmed suspected cases of dementia.

A range of covariates, including race, age, sex, smoking behavior, body mass index (BMI), and the use of aspirin, vitamin B12, and anti-hypertensive medications, were also included in the analysis. Other measurements, such as blood pressure and fasting blood glucose levels, were also obtained to determine the occurrence of hypertension and diabetes, respectively. The calculation of hazard ratios was adjusted for co-morbidities, the use of other medications, and demographic covariates.

Chronic PPI use increases the risk of dementia

Positive associations were observed between the use of PPIs and the risk of dementia; however, these associations were not significant over a median follow-up period of 5.5 years. Nevertheless, the analysis of cumulative PPI use and its association with incident dementia indicated a 33% increased risk of dementia in the later years of life.

Individuals who had been using PPIs for over 4.4 years, while middle-aged have a comparatively higher risk of developing dementia later in life as compared to individuals who did not use PPIs. The association between PPI use and dementia has been explained through two potential mechanisms, including amyloid metabolism impairments and vitamin B12 deficiency.

The use of PPIs has been shown to decrease the levels of vitamin B12, which is essential for cognition. However, adjusting for baseline vitamin B12 supplement use in the current study use did not change the results.

Additionally, studies using murine models have reported increased levels of β-amyloid in the brain after PPI use. PPIs are believed to alter the γ-secretase enzyme, which is involved in β-amyloid cleavage, thereby causing the accumulation of β-amyloid plaques in the brain.


Although a positive association was observed between cumulative PPI use and incident dementia risk, the association was not significant for the current use of PPIs and increased risk of dementia. Further research is needed to elucidate the mechanisms and pathways involved in the development of dementia and its link to PPI use.

Journal reference:
Dr. Chinta Sidharthan

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.


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