The ARIC population is a well-known cohort from four areas in the U.S., and in this analysis included nearly 6,000 participants that had initial visits in the late 1980s, with the most recent visit (visit 5) between 2011-2013. Using visit 5 as a baseline, participants were grouped in two ways; current PPI use (at visit 5), and cumulative PPI use from the previous visits, grouped as 0 days, 1 day – 2.8 years, 2.8-4.4 years, and > 4.4 years. The average follow-up after visit 5 was 5.5 years, with dementia determined by follow-up visits/calls and surveillance of hospital visits, with all cases classified by a panel of physicians and neuropsychologists, a more sensitive approach than relying entirely on ICD codes.
10.2% of study participants developed dementia over the follow-up period. Approximately ¼ of participants were current PPI users (at visit 5), with roughly the same amount having some duration of cumulative use (ranging from 112 days to over 20 years). Current PPI use was associated with a 5-9% increase in risk for dementia, however, this was not a significant finding. Short cumulative use (between 1 day and 4.4 years) was associated with a 9-12% higher risk, but this was also considered insignificant. In contrast, participants in the highest category of cumulative use (>4.4 years) had a significant 38% increase in risk (33% adjusted) for incident dementia. Thus, with a follow-up of only 5 years (participants with dementia before visit 5 were excluded), a significant increase in dementia was observed for people with a longer history of PPI use, though current use or shorter duration of use had non-significant (though positive) associations.
The mechanisms behind this association are not clearly understood and can only be speculated upon. For example, the authors point out that medications that suppress gastric acid production (including PPIs) significantly increase the risk for a vitamin B12 deficiency, with a greater risk for deficiency at higher doses and with a longer duration of use. Lower B12 status has previously been linked to cognitive decline, especially among those with genetic risk for dementia (carriers of an ApoE ε4 allele) or with depression. Markers of B12 status, especially methylmalonic acid, have also been linked to biomarkers for cognitive function and Alzheimer’s disease. It’s worth noting that the Neurology analysis adjusted for ApoE allele status and did assess for B12 intake (4-6% of participants supplemented); they found no influence of B12 supplementation on dementia risk, though duration/dosage was not well-assessed, it’s not clear the number supplementing was adequate to detect a benefit, and B12 status was not evaluated.
The authors also suggest that PPI use may increase β-amyloid levels in the brain, an association well-established in experimental models but not humans. PPI use has also been linked to a greater risk for both ischemic stroke and myocardial infarction, with greater effects observed at higher doses and for longer duration. Similar associations between PPI use and chronic kidney disease have been observed, which may also explain the observed increase in dementia risk. Additionally, PPI use changes the composition of the gut microbiota, and it may be the associated dysbiosis has an influence on dementia risk. Evidence for the “gut-brain axis” as well as a link between altered microbiota composition and multiple neurodegenerative diseases (including dementia) continues to grow, though it is underappreciated. For example, although the link between PPI use and C. difficile infection is well-known, many other changes to the microbiota occur with PPI use, including a reduction in the prevalence of Bifidobacterium and Lactobacillus species.
Multiple other mechanisms may contribute to the observed association between PPI use and dementia. Higher intake as well as higher serum levels of magnesium are likely to have a protective effect, yet PPI use has been linked to both hypomagnesemia and severe hypomagnesemia. Yet despite all the many serious and concerning associations with PPI use, the authors of the recent paper highlight the almost casual nature of their acceptance. While intended to be 1st line therapy for peptic ulcer and GERD, the 4-8 weeks of recommended use is almost always exceeded, despite no approval for long-term use. They were prescribed 115 million times in the U.S. in 2016 (at an increasing rate), not including the over-the-counter use which has become routine. 63% of prescriptions were without a documented GI diagnosis and may have been inappropriate prescriptions. Hopefully, this latest evidence will raise alarm bells, and question their benefit-to-harm ratio closely.