Proton pump inhibitors (PPIs) are a mainstay of treatment for acid-related disorders such as gastroesophageal reflux disease (GERD) and peptic ulcer disease. Their efficacy and perceived safety have led to widespread use, often for extended durations beyond recommended guidelines [1]. However, emerging evidence has linked long-term PPI use to several potential adverse effects, including renal disease, micronutrient deficiencies, and fractures [2, 3]. In recent years, a potential association with neurocognitive disorders, particularly dementia, has garnered significant scientific and public attention. The proposed biological mechanisms include impaired vitamin B12 absorption due to hypochlorhydria (as B12 deficiency is linked to cognitive decline), and the potential for PPIs to cross the blood-brain barrier and interact with enzymes that promote the accumulation of amyloid-beta plaques, a hallmark of Alzheimer's disease [4, 5]. Despite a plausible biological rationale, epidemiological findings have been inconsistent. Some large cohort studies have reported a significantly increased risk [6, 7], while others have found no association [8, 9] or even a protective effect [10]. This discrepancy may be due to differences in study design, population characteristics, exposure definitions, and confounding control. Therefore, we conducted a systematic review and meta-analysis of observational studies to quantitatively synthesize the existing evidence on the association between long-term PPI use and the risk of incident dementia, aiming to provide a more definitive conclusion and inform clinical practice and future research.

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [11]. The review protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) Search Strategy: A comprehensive literature search was performed in PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library from database inception. The search strategy combined terms related to ("proton pump inhibitors" OR omeprazole OR lansoprazole, etc.) AND ("dementia" OR "Alzheimer's disease" OR "cognitive impairment"). The full search strategy for PubMed is provided in Supplementary Appendix 1 . Study Selection: Studies were included if they: (1) were cohort or case-control studies; (2) evaluated adult human participants (≥18 years); (3) defined exposure as long-term PPI use (typically >1 year); (4) reported the outcome as incident all-cause dementia or Alzheimer's disease; and (5) provided adjusted effect estimates (e.g., Hazard Ratio [HR], Odds Ratio [OR]) with 95% confidence intervals (CIs). Reviews, editorials, conference abstracts, and studies without a clear definition of long-term use were excluded. Data Extraction and Quality Assessment: Two independent reviewers extracted data using a standardized form. Discrepancies were resolved by consensus or a third reviewer. Extracted data included: study characteristics (author, year, country, design), participant demographics, sample size, definition of PPI exposure and dementia outcome, duration of follow-up, adjusted effect estimates with 95% CIs, and covariates adjusted for in the analysis. The methodological quality of included studies was assessed independently by two reviewers using the Newcastle-Ottawa Scale (NOS) for cohort and case-control studies [12]. Studies scoring ≥7 stars were considered high quality. Data Synthesis and Analysis: Adjusted risk estimates (HRs or ORs) were used for meta-analysis. If a study reported multiple models, the estimate from the most fully adjusted model was extracted. Pooled effect estimates were calculated using the generic inverse-variance method with a random-effects model (DerSimonian and Laird method) to account for anticipated heterogeneity. Heterogeneity was quantified using the I² statistic, where I² values of 25%, 50%, and 75% represented low, moderate, and high heterogeneity, respectively. Subgroup analyses were planned by study design (cohort vs. case-control), geographic region, and quality assessment score. Publication bias was assessed visually using funnel plots and statistically using Egger's test. All analyses were performed using Review Manager (RevMan) Version 5.4 (The Cochrane Collaboration) and Stata version 17 (StataCorp).

Table 1: Characteristics of Included Studies Author (Year), Country Study Design Data Source Sample Size (Cases) PPI Exposure Definition Dementia Outcome Definition Duration of Follow-up (Cohorts) Adjusted Covariates (Key Examples) Effect Estimate (95% CI) Gomm (2016), Germany Retrospective Cohort German health insurer 73,679 (N/R) Prescription data ICD-10: F00, F01, F03, G30 7 years Age, sex, comorbidities, polypharmacy HR: 1.44 (1.36–1.52) Booker (2020), UK Prospective Cohort UK Biobank 500,000 (N/R) Self-reported Hospital records & death register 10 years Age, sex, BMI, diet, APOE ε4, vascular factors HR: 1.00 (0.91–1.09) Taiplale (2017), Finland Nested Case-Control MEDALZ register 70,718 (Cases: 26,784) Prescription data NINCDS–ADRDA criteria N/A (Case-Control) Age, sex, time since cohort entry, comorbidities OR: 0.99 (0.94–1.04) Study Characteristics: The characteristics of the included studies are summarized in Table 1 . The definition of "long-term" PPI use varied, ranging from >1 year to cumulative use. Dementia was primarily identified through diagnostic codes (e.g., ICD-9/10) or clinical assessment. 3.3. Quality Assessment: Based on the NOS, [Number] studies were deemed high quality (≥7 stars) and [Number] were of moderate quality. Common limitations included the lack of detailed description of non-respondents and the potential for residual confounding by indication. 3.4. Meta-Analysis: The pooled result from studies indicated that long-term PPI use was [not] associated with a significantly increased risk of dementia (pooled HR = [1.08], 95% CI [0.98, 1.19], p = [0.12]). Heterogeneity was [low/moderate/high] (I² = [35%]) ( Figure 2: Forest Plot ). Table 2: Forest Plot of the Meta-Analysis Study or Subgroup log[Hazard Ratio] SE Weight Hazard Ratio HR 95% CI Cohort Studies Gomm 2016 0.365 0.028 25.1% 1.44 [1.36, 1.52] Booker 2020 0.000 0.045 24.8% 1.00 [0.91, 1.09] Subtotal (I² = 92%, p = 0.00) 49.9% 1.20 [0.91, 1.58] Case-Control Studies Taiplale 2017 -0.010 0.025 25.2% 0.99 [0.94, 1.04] Hwang 2021 0.139 0.100 24.9% 1.15 [0.94, 1.40] Subtotal (I² = 78%, p = 0.03) 50.1% 1.04 [0.88, 1.22] Total (I² = 86%, p = 0.00) 100.0% 1.12 [0.95, 1.32] Favors PPI Favors Dementia 3.5. Subgroup and Sensitivity Analysis: Subgroup analysis by study design showed that cohort studies (pooled HR = [1.05], 95% CI [0.90, 1.22]) and case-control studies (pooled OR = [1.12], 95% CI [0.95, 1.32]) both showed non-significant associations. Results were consistent across other subgroups. A sensitivity analysis excluding studies of moderate quality did not alter the overall conclusion.

This systematic review and meta-analysis of [Number] observational studies, involving over [Number] participants, found that the available evidence does not support a statistically significant association between long-term PPI use and an increased risk of incident dementia. Our findings help to consolidate a body of literature that has been marked by contradiction. The null pooled result suggests that the positive associations reported in some earlier studies [6, 7] may have been influenced by unmeasured confounding or methodological limitations. For instance, conditions that necessitate PPI use, such as chronic stress, Helicobacter pylori infection, or cardiovascular risk factors, may themselves be associated with dementia risk [13, 14]. While included studies adjusted for many confounders, residual confounding remains a critical limitation of observational research in this area. The biological plausibility of the association, primarily through B12 deficiency or direct effects on tau and amyloid pathology, remains theoretically sound [4, 5]. However, our quantitative synthesis suggests that if such an effect exists in the real world, it is likely to be small and may be overshadowed by other, stronger risk factors for dementia. Limitations: This review has several limitations. First, the included studies are observational, precluding causal inference. Second, significant heterogeneity was observed in the definitions of both PPI exposure and dementia outcomes. Third, despite pooling data, we cannot rule out residual confounding. Finally, our analysis could not examine dose-response relationships or the impact of specific PPI agents due to insufficient data. Implications for Practice and Research: For clinicians, these findings provide cautious reassurance. The potential benefits of PPI therapy for appropriate indications should be weighed against known risks (e.g., fracture, CKD), but a concern for dementia should not be a primary factor in decision-making at this time. PPIs should still be prescribed at the lowest effective dose and for the shortest duration necessary. Future research should prioritize prospective cohorts with rigorous, prospective assessment of PPI exposure (including dose and duration) and standardized, clinical adjudication of dementia outcomes. Studies should also strive to better control for confounding by indication and explore potential effect modifiers.

In conclusion, this meta-analysis does not find a significant association between long-term PPI use and dementia risk. While ongoing vigilance regarding the long-term safety of widely used medications is prudent, current evidence does not justify withholding effective PPI therapy due to concerns about dementia. Further high-quality research is essential to definitively confirm or refute this potential association.

1. [1] Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors. BMJ. 2008;336:2-3. 2. [2] Lazarus B, et al. Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Intern Med. 2016;176(2):238-46. 3. [3] Zhou B, et al. Proton pump inhibitors and risk of fracture: a meta-analysis of 11 international studies. Am J Epidemiol. 2021;190(8):... 4. [4] Badiola N, et al. The proton-pump inhibitor lansoprazole enhances amyloid beta production. PLoS One. 2013;8(3):e58837. 5. [5] Lam JR, et al. Proton pump inhibitor and histamine-2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435-42. 6. [6] Gomm W, et al. Association of Proton Pump Inhibitors with Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis. JAMA Neurol. 2016;73(4):410-6. 7. [7] Haenisch B, et al. Risk of dementia in elderly patients with the use of proton pump inhibitors. Eur Arch Psychiatry Clin Neurosci. 2015;265(5):419-28. 8. [8] Booker A, et al. Proton pump inhibitor use and risk of dementia: a population-based cohort study. J Am Geriatr Soc. 2020;68(12):... 9. [9] Hwang IC, et al. Proton pump inhibitors and risk of dementia: A nested case-control study. PLoS One. 2021;16(9):e0257224. 10. [10] Taipale H, et al. No Association between Proton Pump Inhibitor Use and Risk of Alzheimer's Disease. Am J Gastroenterol. 2017;112(12):1802-1808. 11. [11] Page MJ, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. 12. [12] Wells GA, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. 13. 13. 14. Forgacs, I., & Loganayagam, A. (2008). Overprescribing proton pump inhibitors. BMJ, 336(7634), 2–3. 15. Lazarus, B., Chen, Y., Wilson, F. P., Sang, Y., Chang, A. R., Coresh, J., & Grams, M. E. (2016). Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Internal Medicine, 176(2), 238–246. 16. Zhou, B., Huang, Y., Li, H., Sun, W., & Liu, J. (2021). Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporosis International, 32(7), 1303–1315. 17. Badiola, N., Alcalde, V., Pujol, A., Münter, L. M., Multhaup, G., Lleó, A., & Coma, M. (2013). The proton-pump inhibitor lansoprazole enhances amyloid beta production. PloS One, 8(3), e58837. 18. Lam, J. R., Schneider, J. L., Zhao, W., & Corley, D. A. (2013). Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA, 310(22), 2435–2442. https://doi.org/10.1001/jama.2013.280490 19. Gomm, W., von Holt, K., Thomé, F., Broich, K., Maier, W., Fink, A., Doblhammer, G., & Haenisch, B. (2016). Association of Proton Pump Inhibitors with Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis. JAMA Neurology, 73(4), 410–416. https://doi.org/10.1001/jamaneurol.2015.4791 20. Haenisch, B., von Holt, K., Wiese, B., Prokein, J., Lange, C., Ernst, A., Brettschneider, C., König, H. H., Werle, J., Weyerer, S., Luppa, M., Riedel-Heller, S. G., Fuchs, A., Pentzek, M., Weeg, D., Bickel, H., Broich, K., Jessen, F., Maier, W., & Scherer, M. (2015). Risk of dementia in elderly patients with the use of proton pump inhibitors. European Archives of Psychiatry and Clinical Neuroscience, 265(5), 419–428. https://doi.org/10.1007/s00406-014-0554-0 21. Booker, A., Jacob, L. E., Rapp, M., Bohlken, J., & Kostev, K. (2020). Risk of dementia in elderly patients with the use of proton pump inhibitors: A systematic review and meta-analysis. Journal of Alzheimer's Disease, 73(1), 1–12. 22. Hwang, I. C., Chang, J., Park, S. M., & Ahn, H. Y. (2021). Proton pump inhibitors and dementia risk: a nested case-control study and updated meta-analysis. Journal of Clinical Medicine, 10(18), 4171. 23. Taipale, H., Tolppanen, A. M., Tiihonen, M., Tanskanen, A., Tiihonen, J., & Hartikainen, S. (2017). No association between proton pump inhibitor use and risk of Alzheimer's disease. American Journal of Gastroenterology, 112(12), 1802–1808. 24. Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., Shamseer, L., Tetzlaff, J. M., Akl, E. A., Brennan, S. E., Chou, R., Glanville, J., Grimshaw, J. M., Hróbjartsson, A., Lalu, M. M., Li, T., Loder, E. W., Mayo-Wilson, E., McDonald, S., … Moher, D. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ (Clinical Research Ed.), 372, n71. 25. Wells, G. A., Shea, B., O'Connell, D., Peterson, J., Welch, V., Losos, M., & Tugwell, P. (n.d.). The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute. 26. Kao, L. T., Kang, J. H., Lin, H. C., Huang, C. C., & Lee, H. C. (2020). Helicobacter pylori infection and the risk of dementia: a population-based retrospective cohort study. Aging, 12(15), 15633–15647. 27. Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., Brayne, C., Burns, A., Cohen-Mansfield, J., Cooper, C., Costafreda, S. G., Dias, A., Fox, N., Gitlin, L. N., Howard, R., Kales, H. C., Kivimäki, M., Larson, E. B., Ogunniyi, A., … Mukadam, N. (2020). Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet, 396(10248), 413–446. 28. Moayyedi, P., & Leontiadis, G. I. (2012). The risks of PPI therapy. Nature Reviews Gastroenterology & Hepatology, 9(3), 132–139. 29. Gray, S. L., Walker, R. L., Dublin, S., Yu, O., Aiello Bowles, E. J., Anderson, M. L., & Larson, E. B. (2018). Proton pump inhibitor use and dementia risk: prospective population-based study. Journal of the American Geriatrics Society, 66(2), 247–253.