Proton Pump Inhibitors and Risk of Mild Cognitive Impairment and Dementia

Felicia C. Goldstein, PhD; Kyle Steenland, PhD; Liping Zhao, MSPH; Whitney Wharton, PhD; Allan I. Levey, MD, PhD; Ihab Hajjar, MD, MS


J Am Geriatr Soc. 2017;65(9):1969-1974. 

In This Article


Figure 1 shows the number of participants initially reviewed for study inclusion. Of 12,416 potential participants with baseline diagnoses of normal cognition and MCI, 1,930 were excluded for reasons outlined in Figure.[1] Of the remaining 10,486 eligible participants, 884 (8.4%) reported always using PPIs, 1,925 (18.4%) reported intermittent use, and 7,677 (73.2%) reported never using PPIs at any annual follow-up.

Figure 1.

Inclusion and exclusion criteria. [Color figure can be viewed at

Table 1 shows the demographic and clinical characteristics of the always, intermittent, and never PPI users. A significantly higher percentage of never PPI users had achieved education levels of high school or more than of those with intermittent PPI use. Always and intermittent PPI users were significantly older than never PPI users. In addition, a significantly higher percentage of always and intermittent PPI users than of never PPI users had heart disease, diabetes mellitus, hypertension, stroke or transient ischemic attack, and depression, and a higher percentage of always and intermittent PPI users took anticholinergic medications. All three groups differed from each other in percentage of H2RA medication use (intermittent>always>never) and number of follow-up visits (intermittent>never>always).

Risk of Cognitive Decline and AD

Whether persons who did not have a dementia diagnosis at baseline were at greater risk of conversion to a diagnosis of cognitive decline (transition from normal cognition to MCI or dementia; transition from MCI to dementia) was first evaluated as a function of PPI use. Always (HR = 0.78, 95% CI = 0.66–0.93, P = .005) and intermittent (HR = 0.84, 95% CI = 0.76–0.93, P < .001) use of PPIs were associated with lower risk of decline in cognitive status after adjusting for potential confounders (Table 2). The NACC database contains information about the suspected etiology of MCI or dementia, allowing whether PPI use was associated with risk of probable AD to be examined. PPI use in the always user group (Table 2) was associated with lower risk of conversion to MCI or dementia due to AD (HR = 0.82, 95% CI = 0.69–0.98, P = .03), as was intermittent use of PPIs (HR = 0.82, 95% CI = 0.74–0.91, P < .001), after adjusting for potential confounders. Figure 2 shows the adjusted survival curves of cognitive decline to MCI or dementia; always PPI users had the highest survival rate, with intermittent users in the middle and never PPI users in the lowest group. Always and intermittent users had rates of survival that were higher than and comparable with those of never PPI users for the transition to MCI or AD (Figure S1A,B).

Figure 2.

Adjusted survival curves of decline in baseline cognition to mild cognitive impairment (MCI) or dementia.

Subgroup Analyses as a Function of Baseline Cognitive Status

Persons with Normal Cognition. Persons diagnosed with normal cognition at baseline (n = 7,404: 613 (8.3%) always users, 1,351 (18.2%) intermittent users, 5,440 (73.5%) never users) were examined separately to determine their relative risk of conversion to cognitive impairment (MCI or dementia) with or without AD etiology. Table S1 shows the relative risk of conversion to MCI or dementia of any etiology (left side) and to an AD etiology (right side), controlling for potential confounders. PPI use in the always user group was associated with lower risk of transition to MCI or dementia with any etiology (HR = 0.73, 95% CI = 0.55–0.97, P = .03) but was not a significant risk factor for an AD etiology (HR = 0.74, CI 0.53–1.04, P = .08). Intermittent PPI use was not a significant risk factor for decline in cognitive status due to any etiology (HR = 0.87, 95% CI = 0.74–1.01, P = .07) or AD etiology (HR = 0.86, 95% CI = 0.71–1.04, P = .13).

Persons with MCI. Of 3,082 persons with MCI at baseline, 271 (8.8%) were always PPI users, 574 (18.6%) were intermittent users, and 2,237 (72.6%) were never users. The relative risk of conversion to dementia of any etiology (HR = 0.86, 95% CI = 0.76–0.98, P = .03) and of an AD etiology (HR = 0.83, 95% CI = 0.73–0.94, P = .01) was significantly lower in intermittent PPI users, whereas the risk of dementia of any etiology (HR = 0.83, 95% CI = 0.67–1.02, P = .08) or of an AD etiology (HR = 0.97, 95% CI = 0.79–1.19, P = .78) was not significantly lower in those who always used PPIs (Table S2).

Association Between Age and PPI Use. The sample was restricted to persons aged 75 and older because prior studies[1,2,5] investigated the risk of cognitive decline in persons in the same age group. The risk of cognitive decline in individuals without dementia but with normal cognition or MCI at baseline (n = 4,562) was significantly lower in intermittent PPI users (HR = 0.85, 95% CI = 0.75–0.96, P = .009), with a similar trend in always users (HR = 0.81, 95% CI = 0.66–1.00, P = .049).