PPIs and Dementia: A Tale of Two Studies – Part Two

PPIs and Dementia: A Tale of Two Studies – Part Two

Prateek Sharma, MD, FASGE, reviewing Northuis C, et al. Neurology 2023 Aug 9.

Previous research has suggested a potential connection between proton pump inhibitors (PPIs) and a higher risk of dementia, causing concern among patients and health care professionals. Many of these studies relied on diagnosis codes to identify cases of dementia and were constrained by incomplete evaluations of PPI usage, as these medications are frequently accessible without a prescription. Two recently published studies have evaluated the association between PPI use and dementia—with divergent conclusions.

This study utilized data from the community-based ARIC (Atherosclerosis Risk in Communities) cohort from 1987 to 2017. The investigators assessed PPI use through medication inventory across clinic visits and annual phone calls. The analysis focused on participants from ARIC visit 5 (2011-2013; visit 1 was 1987-1989) when PPI usage was more common. The investigators used two approaches to examine PPI use: current usage at visit 5 and the duration of usage leading up to visit 5, categorized by exposure periods. The study investigated the development of incident dementia after visit 5, using Cox proportional hazard models, adjusted for various factors.

The analysis comprised 5712 dementia-free participants at visit 5, with a mean age of 75.4 ± 5.1 years, including 22% Black individuals and 58% females. The median follow-up period was 5.5 years, with cumulative PPI use ranging from 112 days to 20.3 years. Throughout the median follow-up duration, there were 585 cases of incident dementia. The findings revealed that participants utilizing PPIs at visit 5 did not face a significantly increased risk of developing dementia during subsequent follow-up, compared with nonusers (hazard ratio [HR], 1.1; 95% confidence interval [CI], 0.9-1.3). However, individuals who had used PPIs for more than 4.4 cumulative years prior to visit 5 exhibited a higher risk of developing dementia during the follow-up period (HR, 1.3; 95% CI, 1.0-1.8) compared with those who reported no PPI use. Notably, the investigators did not observe any significant associations for lesser durations of PPI usage.

Prateek Sharma, MD, FASGE


There is no substantial evidence linking the use of PPI medications to an increased risk of dementia. Although there are anecdotal reports or observational studies suggesting an association between PPIs and cognitive decline, controlled clinical trials designed to investigate this link have generally not shown a clear causal relationship between PPI use and dementia.

It is also important to understand that dementia is a complex condition with multifactorial causes, including genetic predisposition, age-related changes, and various environmental factors. Remember that many patients who take PPIs may also have other risk factors for dementia unrelated to their medication use. Several studies suggesting a link between PPIs and dementia have been criticized for not adequately accounting for other factors (including the one reviewed here) that could contribute to cognitive decline, such as pre-existing health conditions, lifestyle factors, and the use of other medications.

Note to readers: At the time we reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.


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 Aug 9. (Epub ahead of print) (https://doi.org/10.1212/wnl.0000000000207747)

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