Routine use of proton-pump inhibitors (PPIs)—drugs such as Nexium and Prilosec, used to treat heartburn, gastroesophageal reflux disease or peptic ulcers—may cause or accelerate dementia in elderly individuals.
A direct link between PPI use and dementia remains unproved, but the association is plausible and warrants further investigation given the debilitating nature of dementia and lack of effective treatments for it.
As was widely reported in the media in February, German researchers discovered a possible link between PPI use and dementia. The team at the German Center for Neurodegenerative Diseases and elsewhere analyzed health insurance claims records for tens of thousands of elderly individuals, obtained from a large provider of mandatory national health insurance in Germany. They scrutinized filled prescriptions and disease diagnoses for 73,679 individuals who were aged 75 years or older when the study began in 2004. The group included 2,950 participants who were routinely prescribed PPIs and 70,729 who had not used such drugs.
During the course of seven years, 29,510 participants developed some form of cognitive decline, ranging from unspecified dementia to Alzheimer's disease. After adjusting for age, sex, potentially related conditions such as stroke or depression, and use of other prescription drugs, the team found that dementia diagnoses were more common in individuals with regular PPI prescriptions. On average, participants who filled a prescription for a PPI at least once every three months were more than 40 percent more likely to develop dementia than their PPI-free counterparts, according to the paper published online in February in JAMA Neurology.
The results are potentially worrisome considering the number of elderly individuals who take PPIs (recent studies estimate more than one quarter of U.S. nursing home residents use them) and the devastating, difficult-to-treat effects of dementia, says University of Pittsburgh epidemiology researcher Lewis Kuller, who was not involved in the study. In a related editorial in the same issue, Kuller estimated that thousands of otherwise avoidable dementia cases could occur in Germany, assuming the risk reported in the study is accurate, even if only 3 percent of the country's elderly use PPIs.
It is tricky to prove or disprove the proposed PPI-dementia link using an observational study. For example, the researchers were not privy to information that may have offered an alternative explanation for individuals' cognitive deterioration, including genetic risk for Alzheimer's, explains lead investigator Britta Haenisch. People with other risk factors for dementia such as smoking or drinking may also be more likely to use PPIs—and such lifestyle factors were not part of the data. Nor was the team able to adjust for education, which can affect dementia diagnoses.
Haenisch and her colleagues addressed some of these issues in a smaller 2015 study that closely tracked 3,327 individuals, which found an almost 40 percent increase in dementia risk in elderly PPI users. Coupled with earlier studies that show a jump in levels of beta-amyloid protein, a telltale marker of Alzheimer's, in the brains of PPI-treated mice, Kuller says we cannot brush off findings from the latest paper.
“We don't know the cause [of dementia], we don't really understand any specific treatments, it causes a lot of disability, and we have a drug that's very widely used,” Kuller says. “So you have to be more conservative than you would normally be.” That might mean not only planning more targeted studies but also being cautious about overprescribing the drugs to older patients.
How PPIs Might Affect the Brain
PPIs reduce stomach acidity by dialing down the activity of an enzyme that shuttles charged ions through tiny gates—the so-called proton pumps—on the surface of cells lining the stomach. Experts posit that because at least some PPIs have been shown to cross the blood-brain barrier, they may have unanticipated effects on similar enzymes in the brain. Neural support cells called microglia rely on acid-containing organelles to degrade unwanted proteins; inhibiting acid production could impair the cells' ability to break up the protein tangles that are thought to be related to dementia.
Other enzymes related to beta-amyloid proteins may also be affected by the drugs in the brain. Given these plausible pathways, Haenisch explains, the drugs may inadvertently contribute to unhealthy protein accumulation. Studies of PPI-treated mice have confirmed that their brains contain higher levels of beta-amyloid proteins. And Haenisch points out another, simpler connection: PPI use has been linked to lower vitamin B12 availability, which itself has been implicated in cognitive decline.—A.A.