This nationwide nested case-control study indicated prior PPI exposure, regardless of current or past use, use duration, or use of 1st - or 2nd -generation PPIs, increased the likelihood of AD in the >60-year-old Korean population compared to the matched control groups. This adverse impact of PPI use resulting in an increased odds for AD was maintained regardless of age, sex, income, region of residence, smoking, alcohol consumption, blood pressure, fasting blood glucose, total cholesterol, and GERD status. Our results highlight reminding the cautious and strict application of PPI medication following treatment guideline in order to prevent adverse effect of one of the most commonly used medication worldwide.
Despite an increasing number of studies demonstrating the effect of PPI use on risk of dementia, large-scale nationwide studies are limited to AD patients with a history of previous PPI use, and the effects of PPI use on AD are often conflicting. Our findings are in line with results from a prospective multicenter cohort study (AgeCoDe) based on a large population conducted in Germany . Among 3327 persons aged ≥75 years, Haenisch et al. showed that patients receiving PPI medication had a significantly increased risk of AD (hazard ratio 1.44; 95% CI=1.01–2.06) and any dementia (1.38; 95% CI=1.04–1.83) compared with nonusers. A recent community-based study in Spain reported an increased risk of AD (OR 1.47; 95% CI=1.18–1.83) and non-AD dementias (1.38; 95% CI=1.12–1.70) in users of two types of PPIs compared with those who used only one type of PPI , although the authors did not find a higher incidence of AD among the entire sample of PPI users. On the other hand, a prospective population-based study did not find any relations between exposure or duration of PPI use and increased risk of possible or probable AD . However, this study was conducted with volunteers who had at least one follow-up visit for 10 years. Those participants included in the study were likely to care more about their health care and might take more medications than nonparticipants; hence, the generalizability seems limited. A recent study using Taiwan’s health insurance database reported no association between PPI use and AD in older adults . The number of patients with AD (n=428) and controls (n=1,712) were much smaller than those in the present study (17,225 people with AD and 689,000 controls). To avoid selection bias and heterogeneity of the study, we used a methodologically preferable study design using nationwide population-based controls and comprehensively considered the possible confounders. The majority of previous studies that concluded no association of PPI use with dementia did not consider the dementia type in their analysis [18, 32–34]. In our study comprising a nationwide cohort, we were able to reproduce the finding of the link between previous PPI use and AD.
Possible explanations of the involvement of PPIs in AD may find clues in experimental studies [8, 35]. Acidification of lysosomes determines the ability of microglia to degrade β-amyloid . PPIs penetrate the blood-brain barrier in animals and can inhibit vacuolar-type H+–adenosine triphosphatase proton pumps of lysosomes [8, 9, 36], which suppresses the acidification of lysosomes . As a result, PPIs may contribute to the inhibition of acidification, reduced β-amyloid degradation, and enhanced β-amyloid deposition. Of note, PPIs had a greater effect on AD risk in patients using concurrent H2-blockers in the present study, lending support to the theory that blocking acidification may be driving β-amyloid deposits in the brain. PPIs are consumed for long periods in conditions such as GERD, with the resultant exposure of the human brain to a substantial amount of PPIs . Chronic consumption of PPIs may thus be a risk factor for AD . Interestingly, short-term lansoprazole treatment in wild-type and AD transgenic mice dramatically increased β-amyloid levels in a dose-dependent manner . Microglia treated with an ammonia pulse wash for 72 hours were able to degrade a significant amount of β-amyloid in a single day , indicating that artificial lysosomal acidification is capable of affecting the amount of β-amyloid in the acute phase. In addition, PPIs have high binding and selective affinity for misfolded tau protein , indicating that PPIs may have a potential effect in the formation of neurofibrillary tangles of aggregated tau protein in addition to β-amyloid as the pathologic hallmarks of AD [2, 3]. In vitro and in vivo studies have shown that the sulfoxide scaffold found in PPIs has inherent affinity to neurofibrillary tangles in AD and related disorders (e.g., dementia with Lewy bodies and frontotemporal degeneration syndrome) . Nonetheless, clinical trials have failed to show similar adverse effects in dementia . In a placebo-controlled randomized clinical trial (ClinicalTrials.gov number: NCT01776424), the PPI intake group did not show a significant difference in cognitive function when used for 3 years . This discrepancy might imply complicated mechanisms between pharmacological metabolism of PPIs at the levels of cells and cognitive impairments presenting as a phenotype. Since the expression patterns differed between diseases or from subject to subject, there may have been conflicting results regarding the effect of PPIs on cognitive impairments.
Both 1st -generation and 2nd -generation PPIs were associated with an increased likelihood for AD in the present study, which revealed that the associations between PPIs and AD were not different across PPI generations. Consistent with our findings, exposure to any PPI had a significantly increased risk of AD and any dementia [11, 12]. Different PPIs have resulted in elevated risks for dementia including omeprazole (1st -generation) (hazard ratio 1.51; 95% CI=1.40–1.64), pantoprazole (1st -generation) (1.58; 95% CI=1.40–1.79), and esmeprazole (2nd -generation) (2.12; 95% CI=1.82–2.47) . All 1st -generation and 2nd -generation PPIs had a similar negative impact on cognition after short-term exposure to PPIs . Lansoprazole tended to slightly increase the relative risk of AD in the lag window models, although the authors concluded no association of specific PPI drug substances with AD risk . Because both 1st -generation and 2nd -generation PPIs cross the blood-brain barrier, they are able to directly affect the brain [36, 38]. It is evident that all PPIs have some exacerbated effects on cognition .
Strengths and limitations
The strength of this study is its use of a large, representative, nationwide population sample. To our knowledge, this is the largest nationwide nested case-control study to examine the association of PPI use with AD risk. Because the KNHIS-HSC data include all the hospitals and clinics of the entire nation without exception, no medical history was missed during the follow-up period. We comprehensively considered possible confounders. To minimize confounding effects, the control group was randomly selected by matching method. Several limitations of the present study should be taken into account. The length of time for the analysis of PPI prescription, i.e., the 1-year period before the diagnosis of AD, can be considered short. We used prescription days, but actual medication intake could not be monitored in this study. We adjusted variables related to PPI use to minimize confounding effects between PPIs and AD; however, as it is a retrospective design, unmeasured confounding effects could not be completely excluded. Information on the family history of AD and genetic data, including apolipoprotein E4 allele status, was lacking in the health insurance data and was not taken into consideration.