Associations between proton pump inhibitors and Alzheimer’s disease: a nested case–control study using a Korean nationwide health screening cohort

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 75% of cases and mainly affecting elderly individuals [1]. AD is characterized by mixed proteinopathy of abnormal deposits of β-amyloid and tau protein in the brain, leading to neurodegenerative damage [2, 3]. It is a significant physical, emotional, and financial burden on patients, their families, and society [4, 5]. The Korean Dementia Observatory 2020 report indicated a continuous and rapid increase of 30% in the last decade from 2010 to 2019 with aging society [1]. The number of patients affected is expected to rise to over 3 million (16%) by 2050 from 10% of those over 65 years old in Korea in 2019 [1]. Due to the major burden on public health and the lack of curative medication, studies evaluating the neurologic adverse effects of commonly used medications in the elderly population are of great public health importance for dementia prevention.

Proton pump inhibitors (PPIs) are the first choice drugs for treating acid-related diseases and are the most potent inhibitors of gastric acid secretion [6]. These agents suppress gastric acid secretion by irreversible inhibition of H + /K + ATPase on gastric parietal cells [7]. Newer PPIs, such as rabeprazole, ilaprazole, and astemizole, known as 2nd-generation PPIs, are more stable and potent at inhibiting acid secretion than first-generation PPIs (omeprazole, lansoprazole, and pantoprazole) [6]. With the increasing use of PPIs, safety issues regarding PPIs have been raised, and dementia events are one of the major concerns. The association between PPI and dementia is potentially mediated by a PPI-induced increase in the abnormal protein β-amyloid that contributes to the pathophysiology of AD [8, 9] or vitamin B₁₂ deficiency caused by malabsorption induced by PPIs in animal and cell models [10].

Epidemiological research has demonstrated that PPI use could increase dementia events [11‐14], raising concerns of the risk of dementia or cognitive impairment in elderly populations. However, there have been conflicting conclusions regarding the association between PPI use and dementia, specifically AD [15]. Some studies found no significant association between PPIs and dementia [16‐19]. In other studies, the use of PPIs was beneficial in preventing dementia in the elderly [20, 21].

Since evaluating the risk of PPIs on dementia as a whole may mask their effect on AD [22], we designed this study specifically to focus on the impact of PPIs on likelihood for AD. Accordingly, using nationwide Korean National Health Insurance Service-Health Screening Cohort data (KNHIS-HSC), we sought to examine the association between the previous use of PPIs and the risk of dementia in patients with AD compared to a matched control group.

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, may increase the likelihood of AD in the > 60-year-old Korean population compared to the matched control groups. This negative 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 potential 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 [11]. Among 3327 persons aged ≥ 75 years, Haenisch et al. [11] 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 [22], 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 [16]. 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 [17]. The number of patients with AD (n = 428) and controls (n = 1712) 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 potential 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 [8]. 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 [35]. 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 [37]. Chronic consumption of PPIs may thus be a risk factor for AD [37]. Interestingly, short-term lansoprazole treatment in wild-type and AD transgenic mice dramatically increased β-amyloid levels in a dose-dependent manner [9]. Microglia treated with an ammonia pulse wash for 72 h were able to degrade a significant amount of β-amyloid in a single day [8], 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 [38], 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) [39]. Furthermore, recent experimental studies have demonstrated that PPI are potent and selective inhibitors of the acetylcholine-biosynthesizing enzyme, choline acetyltransferase, of which cholinergic dysfunction may cause major dementia disorders in the central nervous system [40] as well as infertility in the spermatic cholinergic system [41]. Nonetheless, clinical trials have failed to show similar adverse effects in dementia [33]. 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 [33]. 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 are 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 (hazard ratio 1.51; 95% CI = 1.40–1.64), pantoprazole (1.58; 95% CI = 1.40–1.79), and esomeprazole (2.12; 95% CI = 1.82–2.47) [12]. All 1st-generation and 2nd-generation PPIs had a similar negative impact on cognition after short-term exposure to PPIs [42]. 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 [43]. 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 [42].

This nationwide population-based data may carefully indicate prior PPI use, regardless of current or past exposure, use duration, or use of 1st- or 2nd-generation PPIs, may increase the likelihood of AD in the > 60-year-old Korean population. Our results may provide supportive evidence regarding previous pharmacoepidemiologic studies of the potential negative impact of PPI on probability of AD.