Long-term proton pump inhibitor use and risk of dementia: a focused review on pantoprazole

Abstract

Background:

Proton pump inhibitors (PPIs) are widely prescribed for acid-related disorders, yet concerns about their long-term effects on cognitive function persist. Emerging evidence suggests a possible association between prolonged PPI use and increased dementia risk, though findings remain inconclusive. This narrative review focuses on pantoprazole, a PPI with unique pharmacokinetics, to assess its potential role in dementia development.

Methods:

A systematic search was conducted using PubMed and PubMed Central with keywords including “dementia,” “proton pump inhibitors,” “Alzheimer’s disease,” and “adverse effects of PPIs,” etc. Studies published from 1 January 2002 to 31 December 2024 were included, focusing on clinical trials, cohort studies, meta-analyses, and systematic reviews. Two independent reviewers assessed eligibility by screening abstracts and full texts, excluding case reports, conference abstracts, and editorial letters.

Results:

Thirteen studies investigating the association between PPI use and dementia were included. Observational studies in Asian populations reported an increased risk, whereas Western studies showed inconsistent results. Mechanistic insights suggest PPIs may contribute to dementia through amyloid-β accumulation, vitamin B12 deficiency, and endothelial dysfunction. Mendelian randomization studies and meta-analyses found no statistically significant association. Pantoprazole’s prolonged acid suppression may differentially influence dementia risk.

Conclusion:

Evidence on the link between long-term PPI use and dementia is conflicting, with variability in study populations and methodological limitations. Further prospective studies and randomized controlled trials are needed to clarify causality. Clinicians should exercise caution, reassess long-term PPI necessity, and consider alternatives to mitigate potential risks.

Introduction

Proton pump inhibitors (PPIs) are a cornerstone therapy for acid-related disorders, including gastroesophageal reflux disease (GERD), peptic ulcers, and Helicobacter pylori eradication, due to their potent inhibition of the gastric H⁺/K⁺-ATPase pump, which suppresses acid secretion^[1,2]. Short-term use is generally recommended, but long-term therapy is often required for severe or refractory conditions, such as Barrett’s esophagus or Zollinger–Ellison syndrome. Overprescribing and inappropriate use, however, are widespread, raising concerns about prolonged exposure and associated adverse effects^[3]. In recent years, long-term PPI use has been linked to potential risks, including kidney disease, fractures, infections, and, notably, neurocognitive impairment and dementia^[2].

HIGHLIGHTS

• Proton pump inhibitors’ (PPI’s) use linked to 22% higher dementia risk in Asian studies.

• Western studies show no consistent PPI–dementia link.

• Pantoprazole may increase amyloid-β and B12 deficiency risks.

• Mendelian studies find no significant PPI–dementia association.

• More prospective trials needed to clarify PPI–dementia causality.

Epidemiological studies have produced conflicting results regarding the association between PPI use and dementia. A Taiwanese cohort study reported a 22% increased dementia risk among long-term PPI users^[4], while a prospective study in the United States and Australia found no such association^[5]. Preclinical evidence supports the hypothesis that PPIs may contribute to dementia risk through biological mechanisms. Animal studies suggest PPIs alter amyloid-β metabolism, leading to its accumulation in the brain, a hallmark of Alzheimer’s disease (AD)^[6]. Additionally, PPIs impair vitamin B12 absorption, and deficiency of this nutrient is associated with cognitive decline^[2,7]. Other proposed mechanisms include endothelial dysfunction and lysosomal proteostasis, which may exacerbate vascular aging and cognitive impairment^[8].

Pantoprazole, a commonly prescribed PPI, is distinguished by its unique pharmacological profile. It binds irreversibly to cysteine 822 of the H⁺/K⁺-ATPase pump, resulting in a prolonged half-life of approximately 46 h, compared to 13 h for lansoprazole and 27 h for omeprazole^[9,10]. Pantoprazole exhibits linear pharmacokinetics, ensuring predictable dose-dependent acid suppression, unlike the nonlinear kinetics of omeprazole and esomeprazole. Its metabolism, primarily via cytochrome P450 enzyme CYP2C19, is less extensive, reducing drug interaction risks. Pantoprazole also demonstrates a faster onset and superior acid suppression compared to omeprazole at standard doses (e.g., 40 mg daily), making it a preferred choice for reliable acid control^[9,10]. These properties, particularly its prolonged acid suppression, may exacerbate vitamin B12 deficiency and amyloid-β accumulation, potentially conferring a distinct dementia risk profile compared to other PPIs.

The global rise in dementia prevalence, with an estimated 55 million cases worldwide in 2020 and projected to reach 78 million by 2030, underscores the urgency of understanding potential risk factors like PPI use. Given pantoprazole’s widespread use and unique pharmacokinetics, this narrative review aims to elucidate whether its prolonged acid suppression contributes uniquely to dementia risk. By synthesizing epidemiological, pharmacological, and mechanistic evidence, this study seeks to inform clinical decision-making, guide safer prescribing practices, and identify research gaps for patients requiring long-term PPI therapy. This study is compliant with the TITAN Guidelines 2025^[11].

Methods

Study design

This narrative review evaluates the association between long-term PPI use, with a specific focus on pantoprazole, and the risk of dementia, including AD.

Search strategy

A comprehensive literature search was conducted using PubMed and PubMed Central to identify studies published between 1 January 2002 and 31 December 2024. Search terms included Medical Subject Headings (MeSH) and free-text terms such as “dementia,” “Alzheimer’s disease,” “proton pump inhibitors,” “pantoprazole,” and “adverse effects of PPIs.” Boolean operators were used, with an example query: (“dementia” OR “Alzheimer’s disease”) AND (“proton pump inhibitors” OR “pantoprazole”) AND (“adverse effects” OR “side effects”). No language restrictions were applied, but only studies with full-text availability in English were included due to resource constraints (Fig. 1). Reference lists of included studies and relevant reviews were manually searched for additional articles.

Figure 1.

PRISMA 2020 flow diagram for study selection process. This flowchart illustrates the systematic review process for studies on long-term proton pump inhibitor (PPI) use and dementia risk, following PRISMA guidelines. It details the identification of records from databases (PubMed, PubMed Central; n = 2), screening of 116 records after removing 6 duplicates, exclusion of 83 reports due to unavailability of full texts, assessment of 33 reports for eligibility, exclusion of 8 reports (5 letters to editor, 2 clinical trials, 1 case report), and inclusion of 25 studies with 13 final reports, conducted from 1 January 2002 to 31 December 2024.

Inclusion and exclusion criteria

Studies were included if they (1) were published between 1 January 2002 and 31 December 2024; (2) were clinical trials, cohort studies, meta-analyses, or systematic reviews; (3) investigated the association between PPI use (with or without focus on pantoprazole) and dementia or AD; and (4) reported quantitative outcomes (e.g., risk ratios, odds ratios [ORs], hazard ratios [HRs]). Excluded studies included (1) case reports, case series, conference abstracts, editorials, or letters; (2) studies lacking a clear focus on dementia or PPI use; (3) studies not reporting original data; and (4) studies with insufficient methodological detail.

Study selection

Search results were exported to Mendeley Reference Manager for deduplication. Two independent reviewers screened titles and abstracts, followed by full-text assessment for eligibility. Discrepancies were resolved through discussion or consultation with a third reviewer. The selection process is documented in a PRISMA flow diagram.

Data extraction

Data were extracted using a standardized template, capturing (1) study characteristics (author, year, country, design, setting, sample size); (2) population details (age, sex, comorbidities); (3) PPI exposure (type, duration, dosage, focus on pantoprazole); (4) dementia outcomes (diagnosis criteria, incidence rates, risk estimates); and (5) confounding factors (e.g., diabetes, cardiovascular disease). For studies not addressing pantoprazole specifically, general PPI data were extracted. Assessments were conducted independently by two reviewers, with disagreements resolved by consensus.

Data synthesis

Due to heterogeneity in study populations, PPI exposure definitions, and dementia assessment methods, a narrative synthesis was conducted. Findings were organized by study design and geographical region, with emphasis on pantoprazole-specific outcomes and mechanistic insights, including amyloid-β accumulation, vitamin B12 deficiency, and endothelial dysfunction.

Results

The search yielded 116 studies, of which 13 specifically investigated the association between PPI use and dementia. Observational studies in Asian populations consistently reported an increased dementia risk with long-term PPI use (Tables 1 and 2). A Taiwanese cohort study of 15 726 participants aged over 45 found a 22% higher dementia risk among PPI users (adjusted HR 1.22, 95% CI 1.05–1.42)^[4]. In contrast, Western studies showed mixed results (Fig. 2). A prospective cohort study of 18 934 older adults in the United States and Australia reported no significant association (HR 0.88, 95% CI 0.72–1.08)^[5]. A Danish nationwide study of 1 983 785 individuals aged 60–75 found an increased risk of all-cause dementia before age 90, with an incidence rate ratio (IRR) of 1.36 (95% CI, 1.29–1.43) for age 60–69 years, 1.12 (1.09–1.15) for 70–79 years, 1.06 (1.03–1.09) for 80–89 years, and 1.03 (0.91–1.17) for those over 90^[12].

Table 1.

Studies that observed the effects of PPIs on dementia or Alzheimer’s disease

No.	Study (first author/year)	Country	Type of study	Study setting	No. of patients	Study period	Result
1	Xie K, 2024	China	Observational study	GWAS database	46 261	-	No link found between PPI use and dementia
2	Wu B, 2024	China	Observational study for Pharmacovigilance	US FDA AERS database	776 191	2004–2023	The authors identified a significant association between dementia and PPIs, except Vonoprazan and Tegoprazan, especially taking competition bias into account.
3	Pourhadi N, 2024	Denmark	Observational study	General population in Denmark	1 983 785	2000–2018	PPI use had no effect on the development of dementia if dementia onset is >90 years of age
4	Khan Z, 2024	India	Secondary research study	SAIL Databank, Wales	183 968	1999–2015	Chronic PPI use can conceal underlying conditions, including cancer, celiac disease, vitamin B12 deficiency, and renal injury, highlighting dementia risk and the need for further investigations on cognitive health
5	Northuis C, 2023	USA	Observational Study	Community-based cohort in the US	5712 dementia-free patients	1987–1989/follow-up from 2006 to 2011	With a minimum cumulative use of PPIs at 111 days and the maximum at 20.3 years, this study Class III evidence that the use of prescribed PPIs for >4.4 years by individuals aged 45 years and older is associated with a higher incidence of newly diagnosed dementia.
6	Mehta R, 2023	USA	Observational cohort study	Community-based cohort in the US and Australia	18 934	2010–2014	The authors found no association between acid suppression and incident dementia, cognitive impairment, and even decline in cognitive function scores over time
7	Zhang P, 2022	China	Experimental study	UK Biobank	501 002	2006–2010	The finding of this large population-based cohort study indicates that the use of proton pump inhibitors is associated with an increased risk of incident dementia, particularly among APOE ε4 heterozygotes.
8	Azhar M, 2021	USA	Secondary research study	Review	-	-	Review suggesting that the association between PPI use and dementia is more cause for alarm than reassurance but treatment plans have to be customized for each patient.
9	Li M, 2019	China	Systematic review	Review of cohort studies	73 679	2019	No statistical association between PPI use and increased risk of dementia or AD.
10	Song Y, 2019	China	Systematic review	Review	642 305	Studies published up to 2018	The current evidence indicates that PPI use does not increase dementia and AD risk
11	Imfeld P, 2018	Switzerland	Observational case control study	Clinical Practice Research Datalink	82 058	19982015	In this large, case-control analysis, the authors did not find any evidence for an increased risk of either AD or VaD related to PPI or H2RA use.
12	Gray S, 2018	USA	Observational cohort study	Kaiser Permanente, Washington	3484	Follow-up period of 7.5 years	Proton pump inhibitor use was not associated with dementia risk, even for people with high cumulative exposure.
13	Tai S, 2017	Taiwan	Observational cohort study	Nationwide study in Taiwan	15 726	2000–2003	Cumulative PPI use was significantly associated with dementia.

Table 2.

Studies documenting potential mechanisms through which proton pump inhibitors may cause damage to organs and the clinical utility of some PPIs in the detection of Alzheimer’s disease

No.	Study (first author/year)	Effect documented
1	Johnson D, 2013	In vivo studies have shown increased cardiovascular adverse effects with concomitant use of PPIs with clopidogrel
2	Badiola N, 2013	Lansoprazole use may exacerbate Aβ amyloid build-up
3	Lam J, 2013	≥2-year supply of PPIs or H2RAs was associated with B12 deficiency
4	Fallahzadeh M, 2010	PPIs may basify lysosomes and hamper the degradation of fAβ
5	Rojo L, 2010	Benzimidazole derivatives – lansoprazole and astemizole – can act as radiotracers in PET neuroimaging in in vivo early detection of Alzheimer’s disease

Figure 2.

Association between long-term proton pump inhibitor (PPI) use and dementia risk across studies and demographics. (A) Forest plot of dementia risk with long-term PPI use by region, showing hazard ratios (HRs) with 95% confidence intervals (CI) from Northus et al (2023, N. America), Gomm et al (2016, Europe), Zheng et al (2022, Asia), Mehta et al (2023, N. America), and Tai et al (2017, Asia). The dashed line represents no effect (HR = 1). (B) Bubble plot of study sample sizes versus HRs for PPI–dementia association, with bubble size proportional to sample size and color indicating region (Northus et al, Gomm et al, Zheng et al, Mehta et al, Tai et al). The dashed line represents no effect (HR = 1). (C) Line graph of dementia risk by duration of PPI use, illustrating HR with 95% CI as a function of cumulative PPI exposure in years. The dashed line represents no effect (HR = 1). (D) Line graph of dementia risk with PPI use across age-groups (Pourhadi et al, 2024), showing incidence rate ratio (IRR) with 95% CI for age-groups 60–69, 70–79, 80–89, and 90+. The dashed line represents no effect (IRR = 1).

Mechanistic studies suggest multiple pathways by which PPIs may contribute to dementia. Preclinical evidence indicates that PPIs, such as lansoprazole, increase amyloid-β production and accumulation in the brain, a hallmark of AD^[13,14]. PPIs inhibit vacuolar-type H⁺-ATPases (V-ATPases) in microglia, reducing lysosomal acidity and impairing amyloid-β clearance, as demonstrated in cellular and animal models^[15]. Long-term PPI use is also associated with vitamin B12 deficiency, a known risk factor for cognitive decline^[16,17]. A case–control study of 25 956 patients reported a 65% increased risk of vitamin B12 deficiency with PPI use for 2 or more years (OR 1.65, 95% CI 1.58–1.73), in comparison to histamine 2 receptor antagonists (OR, 1.25, 95% CI, 1.17–1.34), potentially due to decreased production and cleavage of vitamin B12 binding proteins and gut microbiota overgrowth^[16]. Endothelial dysfunction, linked to lysosomal proteostasis and vascular aging, is another proposed mechanism, with PPIs accelerating endothelial senescence in experimental models^[8].

Mendelian randomization studies and meta-analyses have reported no statistically significant association. A 2019 meta-analysis of over 642 000 participants found no increased risk of dementia (HR = 1.04, 95% CI 0.92–1.15; I² = 95.6%, P < 0.001) or AD with PPI use (HR = 0.96, 95% CI 0.83–1.09; I² = 80.7%, P < 0.001)^[18]. A systematic review similarly found no consistent link^[19]. A 2024 Mendelian randomization study reported no significant association for pantoprazole or lansoprazole after adjusting for false discovery rate (P > 0.05)^[20]. However, a 2024 pharmacovigilance study using disproportionality analysis identified a significant association for most PPIs, except less commonly used agents like vonoprazan and tegoprazan (reporting odds ratio 1.38, 95% CI 1.22–1.56)^[21].

Pantoprazole’s prolonged acid suppression and distinct pharmacokinetics may influence dementia risk differently. Its tight binding to the H⁺/K⁺-ATPase pump and 46-h half-life results in sustained acid suppression, potentially exacerbating vitamin B12 deficiency and amyloid-β accumulation^[9,10]. Pantoprazole-specific data are limited, with most studies examining PPIs collectively. A UK Biobank analysis of 501 002 individuals reported a 20% higher dementia risk among long-term PPI users (HR 1.20, 95% CI 1.07–1.35), with a 46% higher relative risk in APOE ε4 heterozygotes (HR 1.46, 95% 1.22–1.75; P < 0.001), increasing to 68% in those aged 65 and older (HR 1.68, 95% CI 1.36–2.07)^[22]. A German study of 73 679 participants found a 44% increased dementia risk (HR 1.44, 95% CI 1.36–1.52)^[23], while a US study reported a 33% higher risk with over 4.4 years of use (HR 1.33, 95% CI 1.0–1.8)^[6].

Discussion

Prevalence of PPI use and cognitive decline

PPIs have been a mainstay of treatment for acid-related disorders for over three decades, yet their long-term safety, particularly regarding cognitive effects, remains debated. Studies reporting an association between long-term PPI use and dementia are predominantly from Asian populations. The Taiwanese study found a 22% higher dementia risk among PPI users^[4]. The Danish cohort study reported an IRR of 1.36 for dementia in PPI users aged 60–69, decreasing with age, suggesting age-specific effects^[12]. The 2024 pharmacovigilance study minimized competition bias and identified a significant association, except for vonoprazan and tegoprazan^[21]. The UK Biobank analysis highlighted a 20% higher dementia risk, with a 46% higher relative risk in APOE ε4 heterozygotes and a 68% higher risk in those over 65^[22]. A German study reported a 44% increased risk^[23], and a US study found a 33% higher risk with prolonged use^[6].

Conversely, several studies found no association. The 2019 meta-analysis of 642 305 participants concluded that long-term PPI use does not contribute to cognitive decline^[18]. The Adult Changes in Thought study reported no correlation between heavy PPI use (≥3 years) and dementia (HR 0.99, 95% CI 0.75–1.30)^[24]. A UK-based case-control analysis of 41 029 participants aged 65 and above explored whether extended use of PPIs or histamine-2 receptor antagonists was associated with AD or vascular dementia (VaD). The results showed that long-term PPI use (≥100 prescriptions) did not increase the likelihood of developing AD (adjusted odds ratio [aOR] 0.88, 95% CI 0.80–0.97) or VaD (aOR 1.18, 95% CI 1.04–1.33). Likewise, prolonged H2RA use (≥20 prescriptions) was not associated with a higher risk of AD (aOR 0.94, 95% CI 0.87–1.02) or VaD (aOR 0.99, 95% CI 0.89–1.10)^[25]. These discrepancies highlight the complexity of the association and the influence of study design, population, and confounding factors.

A biological perspective

PPI use and amyloid-β deposition

AD, the most common cause of dementia, is characterized by amyloid-β deposition in the cortex^[13]. Long-term PPI use may increase amyloid-β production by inhibiting V-ATPases in microglia (Table 2 and Fig. 3), reducing lysosomal acidity and impairing amyloid clearance^[14]. Lansoprazole enhances amyloid-β production in vitro (Chinese hamster ovary cells) and in vivo (mice)^[13]. Pantoprazole’s prolonged acid suppression may similarly affect amyloid metabolism, though specific data are lacking. Lansoprazole also binds tau aggregates with higher affinity than amyloid-β polymers, suggesting potential diagnostic applications for AD^[26]. Impaired amyloid clearance due to PPI-induced lysosomal dysfunction is a plausible mechanism requiring further human studies.

Figure 3.

Biological mechanisms and study insights on proton pump inhibitor (PPI) use and dementia risk. (A) Pie chart illustrating the proposed biological mechanisms linking PPI use to dementia risk, with proportions attributed to amyloid-β deposition (40%), vitamin B12 deficiency (35%), and endothelial dysfunction (25%). (B) Donut chart showing the proportion of studies reporting a significant (41.7%) versus nonsignificant (58.3%) association between PPI use and dementia. (C) Stacked bar chart depicting the relative emphasis on biological mechanisms in key studies (Baddour et al, 2013; Lam et al, 2013; Yepuri et al, 2016; Ortis-Guerrero et al, 2016), normalized to 1.0, with contributions from amyloid-β deposition, vitamin B12 deficiency, and endothelial dysfunction. (D) Violin plot illustrating the distribution of hazard ratios (HRs) for PPI use and dementia risk by region (Asia, Europe, N. America), with the dashed line representing no effect (HR = 1).

Association of PPI use and vitamin B12 deficiency

Long-term PPI use is associated with vitamin B12 deficiency, a known risk factor for cognitive impairment^[16]. The Kaiser Permanente study reported a 65% increased risk of deficiency with PPI use for 2 or more years, attributed to decreased production and cleavage of vitamin B12 binding proteins and gut microbiota overgrowth from prolonged acid suppression^[16]. Vitamin B12 is essential for myelin production and neurotransmitter synthesis, and its deficiency can lead to neurological damage manifesting as cognitive disturbances, including memory loss and confusion^[17]. The threshold duration and dosage for clinically significant deficiency remain unclear, necessitating further research.

Endothelial dysfunction – a plausible mechanism

Chronic PPI use may decrease lysosomal acidification, leading to proteostasis within vessel walls and endothelial aging, potentially contributing to dementia^[8]. This mechanism, observed in experimental models, suggests PPIs accelerate endothelial senescence, impairing vascular function and increasing dementia risk. Validation in human studies is needed to confirm its clinical relevance.

Epidemiological evidence and clinical studies

Epidemiological studies present conflicting findings, reflecting variability in study populations and methodologies. The German study reported a 44% increased dementia risk among PPI users based on insurance claims data^[23]. The US-based Atherosclerosis Risk in Communities Study found a 33% higher risk with over 4.4 years of use^[6]. In contrast, the prospective cohort study of 18 934 older adults found no significant effect^[5]. A systematic review emphasized the role of confounding factors, such as comorbidities and lifestyle, in observed associations^[27]. A 2020 review highlighted the need for robust clinical trials to clarify the association^[27].

Controversies and confounding factors

Several factors contribute to conflicting findings. Retrospective studies are prone to reverse causality, where cognitive decline may lead to increased PPI use, as patients with early dementia may experience gastrointestinal symptoms requiring PPIs^[14]. Confounding factors, including depression, hyperlipidemia, ischemic heart disease, hypertension, diabetes, and stroke, are common among PPI users and independently increase dementia risk^[4]. Many studies fail to distinguish between short-term and long-term PPI use, and over-the-counter (OTC) PPI use, widespread in many countries, is often underreported, limiting exposure assessment^[5]. Lack of data on genetic factors (e.g., APOE ε4 status), smoking, diet, occupational exposure, educational level, and socioeconomic status further hinders study reliability^[4,5]. Variability in dementia diagnosis criteria (e.g., ICD-10 vs. clinical assessment) and follow-up duration also impacts outcomes.

Clinical implications and recommendations

Given the potential risks, clinicians should adopt a patient-centered approach, incorporating patient preferences into prescribing decisions^[28]. Best practices include the following:

• Regular reassessment of indications for long-term PPI therapy, ensuring valid clinical need (e.g., GERD, peptic ulcers).

• Use of the lowest effective dose to minimize exposure (e.g., pantoprazole 20 mg instead of 40 mg when appropriate).

Deprescribing by gradually tapering PPIs in patients with stable symptoms, using step-down protocols.

• Consideration of alternatives, such as H2-receptor antagonists (e.g., ranitidine, famotidine), dietary modifications (e.g., avoiding trigger foods), or lifestyle interventions (e.g., weight loss, elevating head of bed).

• Monitoring cognitive function in patients on prolonged PPI therapy, especially those with dementia risk factors (e.g., age >65, APOE ε4 carriers, family history).

No explicit guidelines directly link PPI use to dementia risk, but clinical recommendations emphasize careful administration, valid indications, regular reevaluation, and minimizing therapy duration to balance benefits and risks.

Limitations and gaps in literature

This review has several limitations that warrant consideration. First, the reliance on observational studies introduces risks of reverse causality and confounding, as randomized controlled trials (RCTs) are scarce, limiting the ability to establish causality. Second, pantoprazole-specific data are limited, with most studies examining PPIs as a class, which restricts conclusions about pantoprazole’s unique risk profile. Third, OTC PPI use is frequently underreported, leading to potential inaccuracies in exposure estimates and affecting study reliability. Fourth, the narrative synthesis approach may introduce subjectivity in interpreting heterogeneous study findings. Fifth, the lack of clear clinical algorithms or thresholds for deprescribing PPIs or monitoring cognitive effects limits the practical applicability of the findings for clinical decision-making.

Key literature gaps include the following:

1. Robust Clinical Trials: Large-scale RCTs with long-term follow-ups are needed to establish causality between PPI use and dementia. The dose-dependent effects and the impact of different PPI formulations (e.g., immediate vs. delayed-release) remain understudied^[4,12].

2. Mechanistic Uncertainty: There is a lack of human imaging or biomarker studies (e.g., positron emission tomography scans for amyloid burden) to confirm increased amyloid accumulation in long-term PPI users^[6,23]. Additionally, the threshold duration and dosage for clinically significant vitamin B12 deficiency remain unclear^[18].

3. Population-Specific Gaps: Significant associations observed in Asian populations but not in Western ones suggest potential genetic predispositions (e.g., APOE ε4 status, CYP2C19 polymorphisms) that require further investigation^[4]. The Danish study reported a stronger association in younger individuals (60–69 years), with the biological basis unexplored^[12]. Sex-specific differences and interactions with comorbidities are also understudied.

4. OTC Use: Studies focusing on prescribed PPI use often neglect widespread OTC consumption, leading to uncertainty about true exposure levels^[5]. Future research should integrate pharmacy records, self-reported use, and biomarker assessments (e.g., serum B12 levels) to improve exposure accuracy.

5. Clinical Guidance: The absence of clear clinical algorithms or specific thresholds for deprescribing PPIs or monitoring cognitive effects in long-term users hinders the translation of findings into actionable clinical recommendations. Future studies should focus on developing standardized protocols for PPI management in patients at risk of cognitive decline.

Conclusion

The association between long-term PPI use, particularly pantoprazole, and dementia remains inconclusive. Observational studies, particularly in Asian populations, suggest an increased risk, with HRs ranging from 1.20 to 1.44. However, meta-analyses and Western studies often find no significant correlation, with pooled ORs close to 1.0. Proposed mechanisms, including amyloid-β deposition, vitamin B12 deficiency, and endothelial dysfunction, are biologically plausible but require validation in human studies. Conflicting findings stem from methodological limitations, including reverse causality, confounding factors, and underreported OTC use. Pantoprazole’s prolonged acid suppression, due to its 46-h half-life and tight enzyme binding, may exacerbate these risks, but specific data are sparse. Clinicians should prioritize patient-centered care, conducting thorough medication reviews, using the lowest effective dose, and considering alternatives like H2-receptor antagonists or lifestyle interventions, especially in older adults and those with dementia risk factors. Large-scale RCTs, human biomarker studies, and population-specific research are essential to establish causality, validate mechanisms, and inform safer prescribing practices. Until definitive evidence emerges, judicious PPI use, balancing therapeutic benefits with potential cognitive risks, is warranted.

Ethical approval

This study did not require ethical approval as it involves the secondary analysis of previously published, anonymized data available in the public domain. According to the guidelines of the Institution Ethics Committee, reviews that do not involve direct human participation, collection of new data, or access to identifiable patient information are exempt from formal ethical review. Therefore, no specific ethics committee approval or reference number is applicable for this study. The research was conducted in accordance with the principles outlined in the Declaration of Helsinki.

Consent

This review did not require individual patient consent as it utilized secondary data from previously published studies available in the public domain. All included studies were conducted with appropriate ethical approvals and informed consent processes as reported in their respective publications. No new primary data were collected, and no identifiable patient information was accessed or used in this study. The study adheres to ethical standards outlined in the Declaration of Helsinki.

Sources of funding

This study was not funded by any external source.

Author contributions

S.K.: Study concept or design, data extraction, data analysis or interpretation, writing the paper. R.C.: Data analysis or interpretation, writing the paper. G.B.: Data extraction, screening, writing the paper. L.E.: Data analysis, writing the paper. S.G.A.-B.: Screening, writing the paper, draft review and edit. A.H.: Data extraction, screening, writing the paper. I.K.: Visualization, draft review and edit. R.N.: Draft review and edit, supervision.

Conflicts of interest disclosure

The authors declare no conflict of interest.

Guarantor

Dr Ibrahim Khalil.

Research registration unique identifying number (UIN)

Not needed for narrative review.

Provenance and peer review

Not applicable.

Data availability statement

Data will be made available upon request.