Association between proton pump inhibitors and dementia risk: a Mendelian randomization study

Area of Science:

• Pharmacogenomics
• Neuroepidemiology
• Genetic Epidemiology

Background:

• Observational studies suggest a link between proton pump inhibitors (PPIs) and dementia, but causality is unproven.
• Proton pump inhibitors are widely prescribed medications for acid-related gastrointestinal disorders.
• Uncertainty regarding PPIs' cognitive effects necessitates rigorous causal inference studies.

Purpose of the Study:

• To investigate the potential causal relationship between the use of five types of proton pump inhibitors (PPIs) and the risk of all-cause dementia and its subtypes.
• To differentiate direct PPI effects from confounding factors using multivariable Mendelian randomization (MVMR).
• To provide evidence-based guidance on PPI prescription practices concerning cognitive health.

Main Methods:

• Utilized large-scale genome-wide association study (GWAS) data for Mendelian randomization (MR) analysis.
• Performed univariable MR (UVMR) to assess genetic associations between PPIs and dementia.
• Employed multivariable MR (MVMR) to adjust for potential confounders and assess direct effects.
• Conducted heterogeneity, pleiotropy, and leave-one-out analyses to ensure result robustness.

Main Results:

• Initial UVMR suggested potential associations between lansoprazole and pantoprazole with vascular dementia (VD) risk, and frontotemporal dementia (FTD) with rabeprazole use.
• After adjusting for the false discovery rate (FDR), none of the observed associations between PPIs and dementia subtypes remained statistically significant (p_FDR > 0.05).
• MVMR analysis confirmed direct associations for lansoprazole and pantoprazole with VD risk, which also lost significance after FDR correction.

Conclusions:

• This Mendelian randomization study found no robust evidence of a causal relationship between proton pump inhibitor use and an increased risk of dementia.
• The findings suggest that current clinical guidelines recommending PPIs should not be altered based on unsubstantiated concerns about cognitive risks.
• Further research may explore specific genetic predispositions or alternative mechanisms, but current evidence does not support restricting PPI prescriptions due to dementia risk.