Proton Pump Inhibitor Use and Dementia Risk: Prospective Population-Based Study

Abstract

Objectives: To determine whether higher cumulative proton pump inhibitor (PPI) exposure is associated with greater dementia risk.

Design: Prospective population-based cohort study.

Setting: Kaiser Permanente Washington, an integrated healthcare delivery system in Seattle, Washington.

Participants: Individuals aged 65 and older without dementia at study entry (N = 3,484).

Measurements: Participants were screened for dementia every 2 years, and those who screened positive underwent extensive evaluation. Dementia outcomes were determined using standard diagnostic criteria. Time-varying PPI exposure was determined from computerized pharmacy data and consisted of total standardized daily doses (TSDDs) dispensed to an individual in the prior 10 years. We also assessed duration of use. Multivariable Cox regression was used to estimate the association between PPI exposure and time to dementia or Alzheimer's disease (AD).

Results: Over a mean follow-up of 7.5 years, 827 participants (23.7%) developed dementia (670 with possible or probable AD). PPI exposure was not associated with risk of dementia (P = .66) or AD (P = .77). For dementia, the risk for specific levels of cumulative exposure compared to no use was: 365 TSDDs (HR 0.87, 95% CI 0.65-1.18), 1,095 TSDDs (HR 0.99, CI 0.75-1.30) and 1,825 TSDDs (HR 1.13, CI 0.82-1.56). These TSDD levels represent approximately 1, 3 and 5 years of daily use respectively. Duration of PPI use was not associated with dementia outcomes either.

Conclusion: Proton pump inhibitor use was not associated with dementia risk, even for people with high cumulative exposure. Although there are other safety concerns with long-term PPI use, results from our study do not support that these medications should be avoided out of concern about dementia risk.

Keywords: Alzheimer disease; aged; cohort study; dementia; pharmacoepidemiology; proton pump inhibitor.

Figure 1

Association between Cumulative Proton Pump Inhibitor Use and Risk of Incident Dementia. The curve corresponds to estimated adjusted HRs for dementia comparing a given level of proton pump inhibitor exposure (on x-axis) to no exposure (0 TSDDs). Shading corresponds to 95% confidence intervals for the adjusted HR estimates. Y-axis uses a log scale but with corresponding HRs denoted. The minimally adjusted estimates (shown only in the table below the plot) are from a model adjusted only for age and study cohort. The estimates from the primary adjusted model (shown both in the table and the plot) are adjusted for age, study cohort, sex, education, hypertension, diabetes, smoking, stroke, coronary heart disease, body mass index, exercise, self-rated health, depression, gait speed, difficulties with activities of daily living, hospitalizations, and cumulative exposure to nonsteroidal anti-inflammatory medications and anticholinergic medications. 152 (4.4%) participants with missing covariate information were excluded from all model estimates. TSDD, Total Standardized Daily Dose

Figure 2

Association between Cumulative Proton Pump Inhibitor Use and Risk of Incident Alzheimer’s Disease. The curve corresponds to estimated adjusted HRs for Alzheimer’s disease comparing a given level of proton pump inhibitor exposure (on x-axis) to no exposure (0 TSDDs). Shading corresponds to 95% confidence intervals for the adjusted HR estimates. Y-axis uses a log scale but with corresponding HRs denoted. The minimally adjusted estimates (shown only in the table below the plot) are from a model adjusted only for age and study cohort. The estimates from the primary adjusted model (shown both in the table and the plot) are adjusted for age, study cohort, sex, education, hypertension, diabetes, smoking, stroke, coronary heart disease, body mass index, exercise, self-rated health, depression, gait speed, difficulties with activities of daily living, hospitalizations, and cumulative exposure to nonsteroidal anti-inflammatory medications and anticholinergic medications. 152 (4.4%) participants with missing covariate information were excluded from all model estimates. TSDD, Total Standardized Daily Dose