Long-term use of proton pump inhibitors (PPIs) may increase the risk of developing dementia later in life, according to study findings published in Neurology.
Researchers in the United States conducted a community-based cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, from the time of participant enrollment between 1987 and 1989 until 2017. They used visit 5 (conducted between 2011 and 2013) as the baseline for PPI use and calculated incidence of dementia after this visit for a median follow-up of 5.5 years.
PPI use ranged from a minimum of 112 days to a maximum of 20.3 years. During the 5.5-year follow-up period, 585 out of the 5712 participants (58% women; mean age, 75.4) who were dementia-free at visit 5 developed incident dementia.
The researchers observed that PPI users at visit 5 were not more likely to develop incident dementia than nonusers (hazard ratio [HR], 1.1; 95% CI, 0.9-1.3) during the 5.5-year follow-up period.
Compared with individuals who did not use PPIs during the same time frame, those who had used PPIs more than 4.4 cumulative years before visit 5 demonstrated a 33% greater risk of developing incident dementia during the follow-up period (HR, 1.3; 95% CI, 1.0-1.8). This finding suggests that prolonged PPI prescription for over 4.4 years correlated with increased risk for incident dementia in people aged 45 and older.
Scientists have proposed several potential mechanisms underlying the relationship between PPI use and incident dementia.
PPI use may contribute to vitamin B12 deficiency, which is associated with cognitive impairment. PPI use also can impair amyloid metabolism, resulting in onset of Alzheimer disease (AD) due to the increased presence of β-amyloid plaques in the brain.
PPI use also may affect vascular outcomes, contributing to stroke and chronic kidney disease — both of which correlate with higher risk for dementia.
Furthermore, previous research has found PPI use to cause dysbiosis, decreased microbial diversity, and other alterations within the gut microbiome due to hypochlorhydria. These microbiome changes may promote neuroinflammation, oxidative stress, and amyloid-beta aggregation in the brain, frequently co-occurring in patients with dementia and AD.
In a secondary analysis, as an active comparator, the researchers investigated the relationship between PPIs and dementia risk with histamine-2-receptor antagonists (H2RAs). They found that compared with H2RAs, more than 4.4 cumulative years of exposure to PPIs was associated with a greater risk for dementia. However, they did not find an association with short-term or current usage.
The researchers were not able to adjust for anticholinergic medication use due to the alleged associations between those drugs and cognitive impairment because of the small cell sizes.
The researchers wrote, “We found a positive but non-significant association between current use of PPIs and risk of dementia over a median 5.5 years of follow-up.” They concluded, “Long-term cumulative users of PPIs had a 33% increased risk in developing dementia in late life.”
Study limitations included lack of adjustment for all potential confounding factors, lack of generalizability outside of Black and White racial populations, and the inability to continuously measure PPI use throughout the duration of the study, especially given its over-the-counter availability.
Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see original source for full list of disclosures.
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. Published online August 9, 2023. doi:10.1212/WNL.0000000000207747