Cumulative use of proton pump inhibitors (PPIs) — drugs used to help control acid reflux and other gastrointestinal disorders — upped the Risk of dementia, an analysis of 5,700 older adults suggested.

Over a median follow-up of 5.5 years, people in the Atherosclerosis Risk in Communities (ARIC) cohort who used PPIs for more than 4.4 years had a higher risk of dementia (adjusted HR 1.3, 95% CI 1.0-1.8) than those reporting no PPI use, said Kamakshi Lakshminarayan, MD, PhD, of the University of Minnesota in Minneapolis, and co-authors.

Associations were not significant for fewer years of PPI use, the researchers wrote in Neurology.

Long-term use of PPIs has been linked in previous studies to a higher risk of stroke, bone fractures, and chronic kidney disease, Lakshminarayan and colleagues noted. Reports over the years have shown mixed data about PPIs and cognition, however.

In 2016, a prospective study in Germany found a relationship between PPI use and dementia in adults ages 75 and older. More recently, an analysis of data from the ASPREE trial led by Andrew Chan, MD, MPH, of Harvard Medical School and Massachusetts General Hospital in Boston, reported that PPIs were not associated with increased risks of dementia or cognitive decline in people 65 and older.

“I would be cautious about the study’s conclusions that PPI use is associated with risk of dementia,” Chan said. “Importantly, most of their analyses do not support a link. They find an association only in a small subgroup of individuals without a clear linear relationship between duration of use and risk.”

The finding from the ARIC cohort could be due to confounding by other factors associated with the use of these drugs, Chan told MedPage Today. “Taken together with evidence from our recent study that did not find an association in a separate cohort, I think most patients can be reassured that PPI use is not associated with dementia.”

Lakshminarayan and co-authors studied 5,712 people who were dementia-free at baseline, defined as visit 5 (2011-2013) in the ongoing ARIC study. Mean baseline age was 75; 22% of participants were Black, and 58% were female.

During in-person ARIC study visits, participants were asked to bring all over-the-counter and prescription medications used during the preceding 2 weeks. PPI use also was ascertained through annual phone calls. Cumulative PPI use included use from ARIC visit 1 through visit 5. Findings were adjusted for demographics, comorbid conditions, and other medication use.

The researchers divided participants into four groups: those not using PPIs, those using them for up to 2.8 years, those using them for 2.8 to 4.4 years, and those using them for more than 4.4 years.

In total, 1,490 participants used PPIs. Minimum cumulative PPI use was 112 days, and maximum use was 20.3 years. Median use was 3.8 years, and mean use was 4.4 years.

Over a median of 5.5 years, 585 people — roughly 10% of the baseline population — developed dementia. Participants using PPIs at ARIC visit 5 did not have a higher risk of developing dementia than those not using PPIs (adjusted HR 1.1, 95% CI 0.9-1.3). Only those participants who used PPIs for more than 4.4 cumulative years before visit 5 had a higher risk.

In a secondary analysis, Lakshminarayan and co-authors examined the relationship between PPIs and dementia with histamine-2 receptor antagonists (H2RAs) as an active comparator. Results were similar to those of the main analyses: more than 4.4 cumulative years of exposure to PPIs was associated with greater dementia risk compared with H2RAs, but there was no association with use for shorter durations or current use.

The researchers attempted to adjust for anticholinergic medication use due to reported associations between those drugs and cognitive impairment, but were not able to due to small cell size. However, less than 2% of the total sample used anticholinergics at visit 5, they noted. Despite adjusting for many other variables, residual confounding may have influenced results, they acknowledged.