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. J Am Geriatr Soc 66:247-253, 2018.

Reply to: Association Between Proton Pump Inhibitors and Alzheimer's Disease in Older Adults

“…To the Editor: Liao and colleagues 1 report that proton pump inhibitors (PPIs) do not increase the risk of Alzheimer's disease (AD) in older adults, using a case-control series from the Taiwan National Health Insurance database. These findings replicate the conclusions of our study 2 and that of Gray and colleagues, 3 but other studies, 4,5 including another case-control report 6 also in Taiwan using the national database, indicate that PPIs confer a greater risk of developing dementia and AD.…”

“…This is reminiscent of how, several years ago, AEDs were blamed as a cause of an increase in the risk of suicide (Food and Drug Administration warning in January 2008), a claim that many studies have subsequently questioned or minimized. 3 Misinterpretations of the suggested association can have serious consequences by undermining physicians' confidence in prescribing necessary medications and lead to poor adherence, with potential life-threatening consequences.…”

Proton Pump Inhibitors and the Risk of Dementia: Is There a Link?

“…This was the same conclusion as other large studies [3]. However, recently, Gray et al [4] reported that PPI use is not associated with dementia risk, even for people with high cumulative exposure in a prospective population-based study. A prescription sequence symmetry analysis conducted by Park et al [5] also indicated that the risk of PPIs being associated with dementia may be overestimated.…”

“…There is a well-recognized epidemiological link between PPIs and the increased risk of dementia [2, 3]. However, many studies have reported that PPIs are not associated with a greater risk of dementia or AD [4, 5]. But the evidence for this is limited.…”

Drug interactions with dementia‐related pathophysiological pathways worsen or prevent dementia

“…Regarding the dementia risk, initially, three cohort studies Haenisch et al, 2015;Tai et al, 2017) and one crosssectional study (Herghelegiu, Prada, & Nacu, 2016) found a positive association between dementia risk and PPI use. However, this association was not found in more recent studies, including a case control study (Imfeld, Bodmer, Jick, & Meier, 2018) and a cohort study (Gray et al, 2018). One cross-sectional study (de Souto Barreto et al, 2013) and one case control study (Booker, Jacob, Rapp, Bohlken, & Kostev, 2016) even found a decreased risk of dementia with PPI use.…”