A 2023 review article analyzed various studies and meta-analyses to determine whether there was an association between dementia and proton pump inhibitors (PPI) in adult patients without a previous diagnosis of cognitive impairment or dementia. A total of 28 different studies were included for analysis, mostly cohort studies (n= 15) and meta-analyses (n= 7). Only one randomized controlled trial (RCT) was included which found a non-significant increase in dementia with pantoprazole 40 mg versus placebo in atherosclerotic disease patients (odds ratio [OR] 1.20; 95% confidence interval [CI] 0.81 to 1.78; p= 0.36). One meta-analysis suggests a slightly higher risk of dementia from PPI use (hazard ratio [HR] 1.29; 95% CI 1.12 to 1.49) but the others did not support an association, including the most recent meta-analysis consisting of 11 observational studies (N= 642,949) with a HR for dementia from all-cause mortality at 1.11 (95% CI 0.88 to 1.37). Based on these findings, the authors do not suggest there’s a statistically significant association between PPI use and development of cognitive impairment, including dementia. [1]
A 2023 meta-analysis reviewed prospective studies that examined the association between PPI use (compared to non-use or intake of histamine-2 receptor antagonists [H2RA]) and incident dementia (all-cause or Alzheimer’s disease). Nine observational studies were included (N= 3,302,778 individuals; 839,940 PPI users, 2,462,838 non-users; n= 204,108 [6.2%] diagnosed with dementia). The primary meta-analysis showed no evidence of association between PPI use and all-cause dementia, with significant heterogeneity between studies (risk ratio [RR] 1.16; 95% CI 1 to 1.35; I^2= 99%). No differences were seen after adjusting for small-study bias using two different methods as well. A subgroup analysis (n= 3,109,769) did not identify a difference in risk of Alzheimer’s disease between PPI users and non-users (RR 1.15; 95% CI 0.89 to 1.5). A secondary analysis (n= 847,399) showed no association of dementia risk and PPI use vs. H2RA use (RR 1.03; 95% CI 0.66 to 1.62). The authors concluded that the meta-analysis showed no clear evidence for an association between PPI intake and risk of dementia, however they cannot rule out that a potential risk exists. The meta-analysis is limited by the inclusion of mostly observational studies, introducing risk for selection bias and limiting ability to control for confounding variables that may have affected the reported outcomes. [2]
A 2019 meta-analysis included six cohort studies (N= 106,599) that reported the risk of dementia or Alzheimer’s dementia among PPI users vs. non-PPI users. The analysis found a mild increased risk of dementia with PPI use with the pooled relative risk of dementia in PPI users being 1.23 (95% CI 0.9 to 1.67) compared to 1.01 (95% CI 0.78 to 1.32) in non-PPI users, though this difference was not statistically significant (p= 0.19) and significant heterogeneity was observed (p<0.00001, I^2= 95%). A subgroup analysis found increased risk with shorter follow-up duration of <5 years (relative risk 1.62; 95% CI 1.4 to 1.86; p<0.001; I^2= 22%), however in pooled studies of longer follow up (≥ 5 years) found no statistically significant increased risk of dementia with PPI use (relative risk 0.98; 95% CI 0.75 to 1.27; p= 0.87; I^2= 87%). Additionally, subgroups of sample size (<10,000 and ≥ 10,000), did not show an increased risk of dementia in PPI users (relative risk 1.25; 95% CI 0.86 to 1.84; p= 0.23; I^2= 72% and 1.17; 95% CI 0.75 to 1.82; p= 0.48; I^2= 97%, respectively). Overall, the results of analysis suggested no significant association between PPI use and risk of dementia or Alzheimer’s disease. This analysis is limited by the use of only cohort studies due to the risk for selection bias in these studies and the substantial heterogeneity among the included studies. [3]
A 2019 study analyzed the Food and Drug Administration Adverse Event Reporting System database (FAERS/AERS) to provide evidence of an increased association of memory impairment among PPI reports compared to H2RA use as a control. In reports of PPI administration without concurrent medications, there was a significant increase in memory impairment adverse drug reactions (ADRs) compared to H2RA administration (1.29% vs. 0.4%, respectively; OR 3.28; 95% CI 2.31 to 4.67); outcomes included memory impairment, amnesia, Alzheimer’s dementia, and non-Alzheimer's dementia. The H2RA cohort (n= 8,309) did not have any reports of Alzheimer’s dementia, while the PPI cohort (n= 42,537) had 80 reports of Alzheimer’s dementia. PPI use was also significantly associated with a number of neurological ADRs as well, including migraine, peripheral neuropathies, and visual and auditory neurosensory abnormalities. Data provided by FAERS reports should be interpreted with caution, due to over or under reporting, incomplete information, risk of biases, and lack of control over potential confounding variables. A causal relationship cannot be established based on FAERS reports. [4]
A 2022 analysis of the Wisconsin Registry for Alzheimer’s Prevention study, investigated the effects of PPI use and apolipoprotein e4 carrier status on changes in neuropsychological functioning in healthy adults with familial risk factors for dementia. Overall, 1,573 middle aged participants without any symptoms of cognitive decline during the first study visit were included. Data were analyzed for the first four collection periods in 2001, 2006, 2009, and 2012; participants submitted blood samples and completed self-reported questionnaires which inquired about diagnosis of different medical conditions, prescription and non-prescription drug use, tobacco use, and physical activity during each study visit. The Verbal Intelligence Quotient (VIQ) of the Wechsler Abbreviated Scale of Intelligence was used to estimate verbal intelligence. Standardized scores were used for the VIQ only, that compared the participants scores to a normative sample stratified by age, gender, ethnicity, and geographic location. The Mini-Mental State Examination (MMSE) was used to measure orientation and mental status. Working memory was assessed using the Digit Span subtest of the Wechsler Adult Intelligence Scale- Third Edition. The Auditory Verbal Learning Test (AVLT) was used to measure immediate verbal learning (AVLTI) and delayed memory (AVLTD). Psychomotor speed was utilized to assess the Trail Making Test, Part A (TMTA) and cognitive flexibility measured using the Trail Making Test, Part B (TMTB). Study participants were divided into four groups: PPI non-user, stopped PPI, started a PPI, and consistent PPI user. [5]
In terms of covariates evaluated, consistent PPI users were more likely than non-users and those who started or stopped a PPI to report taking an antihypertensive medication. Non-users were more likely than other groups to engage in physical activity at least four times per month. Participants who reported stopping a PPI were more likely than other groups to report using a H2RA. Participants who started or consistently used a PPI were more likely to non-users or those who stopped a PPI to report a history of diabetes, depression, or lung disease. Additionally, consistent PPI users were older than non-users and had lower cholesterol than those who started a PPI. The four groups did not differ in performance on any of the neuropsychological tests during the initial baseline observation. [5]
The linear mixed model results that tested the main effects of H2RA use, PPI use, and APOe4 carrier status did not show that H2RA use was significantly associated with change in performance on any of the neuropsychological tests. In regards to PPI use, main effects assessing PPI use on change in Digit Span, AVLTI, TMTA, and TMTB scores were not significant; change in AVLTD score was significant, but not after adjusting for false discovery rates. In terms of PPI use interaction with APOe4 status, only a significant interaction effect was seen on change in performance on TMTB. APOe4 carriers who stopped PPIs had lower predicted mean TMTB changes score than non-carriers who stopped PPIs. The models did not show any significant interaction effects between PPI use and time or APOe4 carrier status on change in test performance. [5]
The authors concluded that although stopping PPI use may have mild protective effects on executive functioning for non-APOe4 carriers, PPI use was not associated with memory decline in a sample of subjects with familial risk factors for dementia. This study is limited by its retrospective design, inability to differentiate between different PPIs, and that it relied on self-reported data for baseline characteristics and medication history. [5]
A 2017 prospective cohort study investigated the association between PPI use and cognitive function in women. Data were collected from 13,864 participants who completed a self-administered computerized neuropsychological test battery. Psychomotor speed and attention, learning and working memory, and overall cognition was assessed as primary outcome measures. Patients were of a mean age of 61 years old (range 50-70 years) at the time of cognitive testing. Patients who used PPIs tended to be slightly older with higher incidence of chronic medical conditions compared to patients who did not report regular PPI use. PPI users were also less physically active, with higher BMI, lower educational status, and slightly lower dietary quality scores. Initially, a modest association was observed between duration of PPI use and scores for psychomotor speed and attention (mean score difference for PPI use of 9-14 years vs. never used was -0.06; 95% CI -0.11 to 0; p-trend= 0.03). However, after controlling for H2RA use, the score difference was decreased. Additionally, for participants who did not regularly use PPIs, the duration of H2RA use was associated with poorer cognitive scores, with the strongest association apparent for learning and working memory (mean score difference for H2RA users of 9-14 years vs. never used was -0.2; 95% CI -0.32 to -0.08; p-trend<0.001). Ultimately, a convincing association between PPI use and cognitive function was not observed, and the authors concluded that this data does not provide evidence to suggest that PPI use increases dementia risk. [6]