Proton pump inhibitors and dementia: A nationwide population-based study

Abstract

Introduction: Proton pump inhibitors (PPIs) may increase dementia risk. However, it is currently unknown whether timing of exposure or age at dementia diagnosis influence the risk.

Methods: We assessed associations between cumulative PPI use and dementia at different ages in a nationwide Danish cohort of 1,983,785 individuals aged 60 to 75 years between 2000 and 2018.

Results: During follow-up, there were 99,384 all-cause dementia incidences. Incidence rate ratio (IRR) of dementia with PPI ever-use compared with never-use was 1.36 (95% CI, 1.29 to 1.43) for age 60 to 69 years at diagnosis, 1.12 (1.09 to 1.15) for 70 to 79 years, 1.06 (1.03 to 1.09) for 80 to 89 years, and 1.03 (0.91 to 1.17) for 90+ years. Longer treatment duration yielded increasing IRRs. For cases below 90 years, increased dementia rate was observed regardless of treatment initiation up to >15 years before diagnosis.

Discussion: Regardless of timing of treatment initiation, PPI use was associated with increased dementia rate before age 90 years. Dementia rates increased with younger age at diagnosis.

Highlights: After following 1,983,785 individuals for a median of 10 years, 99,384 developed dementia PPIs were used by 21.2% of cases and 18.9% of controls PPI use was associated with increased dementia rate regardless of time of treatment onset Magnitude of associations increased with younger age at diagnosis PPI use was not associated with dementia occurring after age 90 years.

Keywords: Alzheimer's disease; dementia; pharmacoepidemiology; proton pump inhibitor; risk factor.

FIGURE 1

Flowchart of the establishment of the cohort and nested case‐control population. During follow‐up, 486,312 individuals were censored due to emigration (n = 11,970) or death (n = 474,342).

FIGURE 2

Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of the association between cumulative duration of proton pump inhibitor (PPI) use and all‐cause dementia. Adjustments were made for educational level, cardiovascular disease, diabetes, hypertension, and dyslipidemia, with a 5‐year lag time window applied. Estimates for “one prescription only” are not shown.

FIGURE 3

Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of the association between timing of initiation of proton pump inhibitor (PPI) use and all‐cause dementia. Adjustments were made for educational level, cardiovascular disease, diabetes, hypertension, and dyslipidemia. Asterisks (*) denote that for the category of “<= 5 years before index” there was no 5‐year lag time window applied, whereas a 5‐year lag time window was applied for all other categories. Estimates for “one prescription only” are not shown.