Proton pump inhibitors: the impact on cognitive health in older adults
DOI:
https://doi.org/10.24265/horizmed.2024.v24n1.11Keywords:
Omeprazole, Esomeprazole , Lansoprazole , Pantoprazole , Dementia , Cognitive Dysfunction, DepressionAbstract
Proton pump inhibitors (PPIs) are the most potent drugs to inhibit gastric acid secretion, being used in the treatment of most inflammatory conditions of the gastric mucosa. They are among the most prescribed and overprescribed medications worldwide; for example, in the United States, according to the National Health and Nutrition Examination Survey, they almost doubled their use in adults aged 40 years and older from 4.9 % to 8.3 % between 1999 and 2012. Although they are generally considered well tolerated, some epidemiological studies extracting information from large databases have reported a number of adverse effects associated with their prolonged use, including cognitive impairment, chronic kidney disease, myocardial infarction, stroke, bone fractures and even death, among others. The objective was to conduct a narrative review of the literature on the effects of chronic use of PPIs on cognitive impairment in older adults. Articles were reviewed based on a search in the PubMed, Scopus and SciELO databases using both English and Spanish keywords and related MeSH/DeCS terms. Neurological side effects induced by chronic PPI use may be indirectly related to secondary systemic disorders (magnesium and vitamin B12 deficiency) or to direct effects on neuronal functioning after passing through the blood-brain barrier. Although several neurobiological mechanisms by which PPIs could favor the development of dementia—which involve Tau protein function, beta-amyloid [βA] accumulation and cobalamin deficiency, among others—have been described, most of the available clinical evidence has not shown a significant association between PPI use and the risk of dementia or cognitive impairment. To establish the adverse clinical effects of chronic PPI use more clearly, especially on brain functioning, well-designed cohort studies with large sample sizes and long follow-up periods, with a reliable method to adjust for standardized confounders, as well as subgroup analyses are needed.
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References
Strand DS, Kim D, Peura DA. 25 years of proton pump inhibitors: a comprehensive review. Gut Liver. 2017;11(1):27-37.
Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL. Trends in prescription drug use among adults in the United States from 19992012. JAMA. 2015;314(17):1818-31.
Goldstein FC, Steenland K, Zhao L, Wharton W, Levey AI, Hajjar I. Proton pump inhibitors and risk of mild cognitive impairment and dementia. J Am Geriatr Soc. 2017;65(9):1969-74.
Schubert ML. Adverse effects of proton pump inhibitors: fact or fake news? Curr Opin Gastroenterol. 2018;34(6):451-7.
Sheen E, Triadafilopoulos G. Adverse effects of long-term proton pump inhibitor therapy. Dig Dis Sci. 2011;56(4):931-50. 6. Voet D, Voet JG. Bioquímica. 3a ed. España: Editorial Médica Panamericana; 2006.
Ward RM, Kearns GL. Proton pump inhibitors in pediatrics: mechanism of action, pharmacokinetics, pharmacogenetics, and pharmacodynamics. Paediatr Drugs. 2013;15(2):119-31.
Cardona-Ospina JA, Medina-Morales DA, Rodríguez-Morales AJ, Machado-Alba JE. Evidence based medicine perspective on long-term adverse effects of proton pump inhibitors. Rev Col Gastroenterol. 2016;31(4):398-403.
Asociación Americana de Psiquiatría. Manual diagnóstico y estadístico de los trastornos mentales (DSM-5®). 5a ed. Arlington: Editorial Médica Panamericana; 2014.
Laudisio A, Antonelli Incalzi R, Gemma A, Giovannini S, Lo Monaco MR, Vetrano DL, et al. Use of proton-pump inhibitors is associated with depression: a population-based study. Int Psychogeriatr. 2018;30(1):153-9.
Caselli RJ. Current issues in the diagnosis and management of dementia. Semin Neurol. 2003;23(3):231-40.
Morris JC. Dementia update 2003. Alzheimer Dis Assoc Disord. 2003;17(4):245-58.
Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673-734.
Biessels GJ, Despa F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol. 2018;14(10):591-604.
Ungvari Z, Toth P, Tarantini S, Prodan CI, Sorond F, Merkely B, et al. Hypertension-induced cognitive impairment: from pathophysiology to public health. Nat Rev Nephrol. 2021;17(10):639-54.
GBD 2016 Dementia Collaborators. Global, regional, and national burden of alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2019;18(1):88-106.
Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement. 2007;3(3):186-91.
Aarsland D. Epidemiology and pathophysiology of dementia-related psychosis. J Clin Psychiatry. 2020;81(5):AD19038BR1C.
Carrillo MC, Dean RA, Nicolas F, Miller DS, Berman R, Khachaturian Z, et al. Revisiting the framework of the National Institute on AgingAlzheimer's Association diagnostic criteria. Alzheimers Dement. 2013;9(5):594-601.
Ortiz-Guerrero G, Amador-Muñoz D, Calderón-Ospina CA, LópezFuentes D, Nava Mesa MO. Proton pump inhibitors and dementia: physiopathological mechanisms and clinical consequences. Neural Plast. 2018;2018:5257285.
Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases. J Am Pharm Assoc (Wash). 2000;40(1):52-62.
Novotny M, Klimova B, Valis M. PPI long term use: risk of neurological adverse events? Front Neurol. 2019;9:1142.
De la Vega R, Zambrano A. Hipocampo.org®. 2023 [citado el 20 de octubre de 2023]. Enfermedad de Alzheimer: parte 11. Disponible en: https://www.hipocampo.org/alzheimer.asp
Badiola N, Alcalde V, Pujol A, Münter LM, Multhaup G, Lleó A, et al. The proton-pump inhibitor lansoprazole enhances amyloid beta production. PLoS One. 2013;8(3):e58837.
Fallahzadeh MK, Borhani Haghighi A, Namazi MR. Proton pump inhibitors: predisposers to Alzheimer disease? J Clin Pharm Ther. 2010;35(2):125-6.
Maccioni RB, Cambiazo V. Role of microtubule-associated proteins in the control of microtubule assembly. Physiol Rev. 1995;75(4):835-64.
Wegmann S, Biernat J, Mandelkow E. A current view on Tau protein phosphorylation in Alzheimer's disease. Curr Opin Neurobiol. 2021; 69:131-8.
Rojo LE, Fernández JA, Maccioni AA, Jimenez JM, Maccioni RB. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer's disease. Arch Med Res. 2008;39(1):1-16.
Okamura N, Suemoto T, Furumoto S, Suzuki M, Shimadzu H, Akatsu H, et al. Quinoline and benzimidazole derivatives: candidate probes for in vivo imaging of tau pathology in Alzheimer's disease. J Neurosci. 2005;25(47):10857-62.
Fawaz MV, Brooks AF, Rodnick ME, Carpenter GM, Shao X, Desmond TJ, et al. High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection. ACS Chem Neurosci. 2014;5(8):718-30.
Forrelat M, Gomis I, Gautier H. Vitamina B12: metabolismo y aspectos clínicos de su deficiencia. Rev Cubana Hematol Inmunol Hemoter. 1999;15(3):159-74.
Ma F, Wu T, Zhao J, Ji L, Song A, Zhang M, et al. Plasma homocysteine and serum folate and vitamin B12 levels in mild cognitive impairment and alzheimer's disease: a case-control study. Nutrients. 2017;9(7):725.
Moore E, Mander A, Ames D, Carne R, Sanders K, Watters D. Cognitive impairment and vitamin B12: a review. Int Psychogeriatr. 2012;24(4):541-56.
Zhang DM, Ye JX, Mu JS, Cui XP. Efficacy of vitamin B supplementation on cognition in elderly patients with cognitive-related diseases. J Geriatr Psychiatry Neurol. 2017;30(1):50-9.
Rafiee S, Asadollahi K, Riazi G, Ahmadian S, Saboury AA. Vitamin B12 inhibits tau fibrillization via binding to cysteine residues of tau. ACS Chem Neurosci. 2017;8(12):2676-82.
Lauer AA, Grimm HS, Apel B, Golobrodska N, Kruse L, Ratanski E, et al. Mechanistic link between vitamin B12 and Alzheimer’s disease. Biomolecules. 2022;12(1):129.
Mandelkow EM, Mandelkow E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med. 2012;2(7):a006247.
Hashioka S, Klegeris A, McGeer PL. Proton pump inhibitors exert antiinflammatory effects and decrease human microglial and monocytic THP-1 cell neurotoxicity. Exp Neurol. 2009;217(1):177-83.
Hashioka S, Klegeris A, McGeer PL. Proton pump inhibitors reduce interferon-γ-induced neurotoxicity and STAT3 phosphorylation of human astrocytes. Glia. 2011;59(5):833-40.
Haenisch B, von Holt K, Wiese B, Prokein J, Lange C, Ernst A, 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.
Gomm W, von Holt K, Thomé F, Broich K, Maier W, Fink A, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73(4):410-6.
Tai SY, Chien CY, Wu DC, Lin KD, Ho BL, Chang YH, et al. Risk of dementia from proton pump inhibitor use in Asian population: A nationwide cohort study in Taiwan. PLoS One. 2017;12(2):e0171006.
Gómez C, Borda MG, Pérez MU, Tella-Vega P, Cano-Gutiérrez CA. Asociación entre uso de inhibidores de bomba de protones y deterioro cognitivo en adultos mayores. Univ Med. 2019;60(1).
Batchelor R, Gilmartin J, Kemp W, Hopper I, Liew D. Dementia, cognitive impairment and proton pump inhibitor therapy: a systematic review. J Gastroenterol Hepatol. 2017;32(8):1426-35.
Li M, Luo Z, Yu S, Tang Z. Proton pump inhibitor use and risk of dementia: systematic review and meta-analysis. Medicine (Baltimore). 2019;98(7):e14422.
Song YQ, Li Y, Zhang SL, Gao J, Feng SY. Proton pump inhibitor use does not increase dementia and Alzheimer's disease risk: An updated meta-analysis of published studies involving 642305 patients. PLoS One. 2019;14(7):e0219213.
Zhang Y, Liang M, Sun C, Song EJ, Cheng C, Shi T, et al. Proton pump inhibitors use and dementia risk: a meta-analysis of cohort studies. Eur J Clin Pharmacol. 2020;76(2):139-47.
Hussain S, Singh A, Zameer S, Jamali MC, Baxi H, Rahman SO, et al. No association between proton pump inhibitor use and risk of dementia: Evidence from a meta-analysis. J Gastroenterol Hepatol. 2020;35(1):19-28.
Desai M, Nutalapati V, Srinivasan S, Fathallah J, Dasari C, Chandrasekhar VT, et al. Proton pump inhibitors do not increase the risk of dementia: a systematic review and meta-analysis of prospective studies. Dis Esophagus. 2020;33(10):doaa041.
Cooksey R, Kennedy J, Dennis MS, Escott-Price V, Lyons RA, Seaborne M, et al. Proton pump inhibitors and dementia risk: Evidence from a cohort study using linked routinely collected national health data in Wales, UK. PLoS One. 2020;15(9):e0237676.
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