Use of proton pump inhibitor drugs is associated with increased dementia risk in users with an increasing impact with longer duration of use, a major cohort study has found.

With PPI uptake increasing rapidly over the past few decades, particularly in younger adults, the growing body of evidence related to potential serious adverse effects call for scientific attention, according to the investigators.

The study assessed associations between cumulative use of the agents and dementia at different ages in a nationwide Danish cohort of almost 2 million individuals aged 60-75.

All up, there were 99,384 instances of dementia identified in the group between 2000 and 2018, with PPIs used by 21.2% of cases compared with 18.9% of matched controls.

Importantly, use of PPIs was associated with increased risk of dementia at all ages of diagnosis up until 90 years, the researchers reported in Alzheimer’s & Dementia (link here).

When broken down by decade, patients who had previously used PPIs were 36% more likely to be diagnosed with dementia in their 60s than matched controls.

“We consistently observed higher dementia rates with younger age at dementia diagnosis,” the study investigators noted.

They were also 12% more likely to be diagnosed in their 70s and 3% more likely to be diagnosed in their 80s, the researchers said.

Rates of dementia diagnosis at age 90 or older were also slightly higher in PPI users, although this finding was not statically significant.

Interestingly, dementia diagnosis frequently occurred within three months of PPI initiation at all ages.

This could represent an acceleration of dementia neuropathy related to PPI use, but were more likely influenced by reverse causation, according to the researchers.

“Nevertheless, PPI initiation up to >15 years before dementia diagnosis consistently yielded increased dementia rates before age 90 years, potentially indicative of a long-acting influence of PPIs on the brain in congruence with underlying neurobiological processes leading to dementia which expectedly progress gradually over decades,” they wrote.

The authors theorised the observed association between cumulative PPI exposure and increased dementia rate could be explained by PPI-related impacts on cognition, potentially through neurodegeneration, cerebrovascular damage, or both.

Nevertheless, PPI initiation up to >15 years before dementia diagnosis consistently yielded increased dementia rates before age 90 years, potentially indicative of a long-acting influence of PPIs on the brain in congruence with underlying neurobiological processes leading to dementia which expectedly progress gradually over decades.

“PPIs can affect brain cells through various mechanisms, for example, by increasing beta-amyloid levels, involved in the development of AD,” they noted.

“Long-term exposure may additionally increase vascular dysfunction by impairing endothelial function, thereby accelerating the progression of cerebrovascular damage potentially leading to vascular dementia.”

They added: “Further studies are warranted to determine if these findings represent a causal effect of PPIs on dementia risk, and to explore risk differences according to age at dementia diagnosis and dementia subtypes.”