Proton Pump Inhibitors Versus H2 Blockers and the Risk of Incident Dementia in Adults Younger Than 65

Background: Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2 blockers) are routinely prescribed for the long-term management of chronic acid-related gastrointestinal conditions. Although prior research has explored a potential link between PPI exposure and cognitive decline, findings across studies have been inconsistent, and most investigations have concentrated on elderly populations. Objective: This study aimed to evaluate whether PPI therapy, relative to H2 blocker therapy, was associated with differential incident dementia risk among adults below the age of 65 who carry diagnoses warranting sustained acid suppression. Methods: A retrospective cohort analysis was performed using data from the TriNetX Global Collaborative Network. Eligible participants were adults aged 18-65 with a confirmed diagnosis of gastroesophageal reflux disease with esophagitis (ICD-10-CM K21.0) or Barrett's esophagus (ICD-10-CM K22.7), and documented treatment with either a PPI (ATC code A02BC) or an H2 blocker (ATC code A02BA). All individuals with pre-existing dementia were excluded. Cohorts were balanced via 1:1 propensity score matching on age, sex, and baseline psychiatric and neurodevelopmental diagnoses. The main outcome, incident dementia, was captured through ICD-10 diagnostic codes encompassing Alzheimer's disease (G30), dementia secondary to other diseases (F02), unspecified dementia (F03), and other degenerative nervous system disorders (G31). Analyses included risk ratios, odds ratios, Kaplan-Meier survival curves, and Cox proportional hazards regression. Results: Following propensity score matching, each treatment group comprised 197,187 patients. New-onset dementia was recorded in 368 individuals (0.19%) assigned to the PPI group and 607 individuals (0.31%) in the H2 blocker group. Relative to H2 blocker use, PPI therapy was linked to a meaningfully lower likelihood of developing dementia (risk ratio 0.61, 95% CI 0.53-0.69; odds ratio 0.61, 95% CI 0.53-0.69). Kaplan-Meier analyses corroborated these findings, with a significantly reduced dementia hazard observed among PPI-treated patients (hazard ratio 0.63, 95% CI 0.55-0.72; log-rank p < 0.001). Conclusion: In this propensity-matched sample of adults younger than 65 years with chronic acid-related diagnoses, PPI therapy did not elevate the risk of incident dementia relative to H2 blockers and was, in fact, associated with a statistically lower observed risk. These results should reassure clinicians and patients regarding the cognitive safety profile of PPIs when sustained acid suppression is medically necessary.