Signal and Noise: Proton Pump Inhibitors and the Risk of Dementia?

Abstract

The association between proton pump inhibitor (PPI) use and dementia remains controversial. This cohort study re-examines this issue, addressing shortcomings identified in previous publications using a population-based and a high-dimension propensity-score matched cohort to follow patients for up to 22 years. Cox regression models using baseline characteristics, a lag period, and time-varying variables were used to examine the risk of dementia by cumulative PPI exposure. High-dose PPI users (> 180 days of use) had significantly higher risk of dementia in crude Cox models. After adjustment for medical diagnoses and prescription drug use, these associations disappeared. Among high-dose users starting PPI therapy between 46 and 55 years old, the unadjusted hazard ratio (HR) was 1.55 (95% confidence interval (CI) 1.14, 2.10); the adjusted hazard ratio (aHR) was 1.10 (95% CI 0.80, 1.51). For high-dose users starting therapy between 56 and 65 years, HR = 1.22 (95% CI1.03, 1.44); aHR = 0.99 (95% CI 0.83, 1.17). High-dose users between the ages of 66 and 75 years had no association with the risk of dementia. The use of lag models or time-varying parameters similarly found some association with dementia in crude, but not multivariable Cox models. Although high-dose PPI users were more likely to develop dementia, they were more likely to be diagnosed with dementia risk factors, such as diabetes and cardiovascular disease, which are risk factors for dementia. Controlling for these conditions using multivariable models or a propensity-score matched cohort eliminated this association.

Proton Pump Inhibitor as Proxy for Increased Dementia Risk

“…Our results are similar to those published recently by Friesen et al, who suggested PPI use as a marker for poor health status 19 . We similarly assumed that the effect of PPIs was cumulative and nonreversible, as dementia is a neurodegenerative condition.…”

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

“…based on registers from one Canadian province followed three cohorts with different age groups at study start and found highest risk estimates for dementia with PPI use in the youngest cohort (start age 46 to 55 years). 24 Although the authors did not stratify by age at dementia diagnosis, this aligns with our study results displaying higher dementia rates occurring at a younger age. Overall, Friesen et al.…”

“…Previous studies investigating the association between PPIs and risk of dementia reported conflicting findings with some studies reporting a positive association, 18 , 19 , 20 , 21 while other studies showed a negative or neutral association. 22 , 23 , 24 This could possibly be owing to the heterogeneity between data availability and study design. 25 …”

“…Previous studies investigating the association between PPIs and risk of dementia reported conflicting findings with some studies reporting a positive association, [18][19][20][21] while other studies showed a negative or neutral association. [22][23][24] This could possibly be owing to the heterogeneity between data availability and study design. 25 Although not specifically designed to investigate risk differences according to age at dementia diagnosis, two previous studies observed greater risk estimates among the youngest cases of dementia compared to older cases.…”

“…25 Although not specifically designed to investigate risk differences according to age at dementia diagnosis, two previous studies observed greater risk estimates among the youngest cases of dementia compared to older cases. 18,20 However, most previous studies did not take this into account, 19,[21][22][23][24] and thus, the association between PPI use and dementia risk in relation to age at dementia diagnosis remains largely unexplored.…”