Abstract

Proton pump inhibitors (PPIs) are widely prescribed for long-term management of acid-related disorders. Preclinical studies suggested potential neurotoxic mechanisms, but the clinical evidence regarding an association with dementia risk remains highly controversial. This systematic review aimed to critically appraise and synthesize the current evidence on the association between long-term PPI use and the risk of incident dementia. A systematic literature search was conducted. Observational studies and pharmacovigilance reports investigating long-term PPI use (≥1 year) and incident dementia in adults were included. Out of 632 initial records, 21 studies were included. The findings were highly inconsistent. Several large observational studies reported a significant positive association (Hazard Ratios ranging from 1.20 to 1.85), particularly with cumulative use. Conversely, other high-quality studies, including a prospective cohort trial with clinician-adjudicated outcomes and large distributed network analyses, found no association. Two studies even reported a statistically significant reduction in dementia risk among PPI users. Mendelian randomization studies found no robust evidence for a causal relationship. The discordance was systematically tied primarily to methodological limitations, with positive signals primarily emerging from studies susceptible to residual confounding (e.g., confounding by indication) and immortal time bias. The current evidence on the association between long-term PPI use and dementia is conflicting and inconclusive. The observed associations appear highly sensitive to methodological approach, and the most robust studies predominantly find no causal link. Therefore, concerns about dementia risk should not dictate clinical decision-making for PPI therapy, which should continue to be guided by established benefits and proven risks.

Key words: Proton pump inhibitors, dementia, cognitive decline, long-term adverse effects, systematic review.