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Risk of dementia in elderly patients with the use of proton pump inhibitors

  • Britta Haenisch
  • Klaus von Holt
  • Birgitt Wiese
  • Jana Prokein
  • Carolin Lange
  • Annette Ernst
  • Christian Brettschneider
  • Hans-Helmut König
  • Jochen Werle
  • Siegfried Weyerer
  • Melanie Luppa
  • Steffi G. Riedel-Heller
  • Angela Fuchs
  • Michael Pentzek
  • Dagmar Weeg
  • Horst Bickel
  • Karl Broich
  • Frank Jessen
  • Wolfgang Maier
  • Martin Scherer
Original Paper

Abstract

Drugs that modify the risk of dementia in the elderly are of potential interest for dementia prevention. Proton pump inhibitors (PPIs) are widely used to reduce gastric acid production, but information on the risk of dementia is lacking. We assessed association between the use of PPIs and the risk of dementia in elderly people. Data were derived from a longitudinal, multicenter cohort study in elderly primary care patients, the German Study on Aging, Cognition and Dementia in Primary Care Patients (AgeCoDe), including 3,327 community-dwelling persons aged ≥75 years. From follow-up 1 to follow-up 4 (follow-up interval 18 months), we identified a total of 431 patients with incident any dementia, including 260 patients with Alzheimer’s disease. We used time-dependent Cox regression to estimate hazard ratios of incident any dementia and Alzheimer’s disease. Potential confounders included in the analysis comprised age, sex, education, the Apolipoprotein E4 (ApoE4) allele status, polypharmacy, and the comorbidities depression, diabetes, ischemic heart disease, and stroke. Patients receiving PPI medication had a significantly increased risk of any dementia [Hazard ratio (HR) 1.38, 95 % confidence interval (CI) 1.04–1.83] and Alzheimer’s disease (HR 1.44, 95 % CI 1.01–2.06) compared with nonusers. Due to the major burden of dementia on public health and the lack of curative medication, this finding is of high interest to research on dementia and provides indication for dementia prevention.

Keywords

Dementia Proton pump inhibitors Risk factor Elderly Prevention 

Notes

Acknowledgments

This study is part of the German Research Network on Dementia (KND) and the German Research Network on Degenerative Dementia (KNDD) and was funded by the German Federal Ministry of Education and Research (Grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; Grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716).

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Ziegler U, Doblhammer G (2009) Prevalence and incidence of dementia in Germany—a study based on data from the public sick funds in 2002. Gesundheitswesen 71:281–290PubMedCrossRefGoogle Scholar
  2. 2.
    Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M, Alzheimer’s Disease International (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366:2112–2117PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Reitz C, Brayne C, Mayeux R (2007) Epidemiology of Alzheimer disease. Nat Rev Neurol 7:137–152CrossRefGoogle Scholar
  4. 4.
    Wimo A, Jönsson L, Bond J, Prince M, Winblad B, Alzheimer Disease International (2013) The worldwide economic impact of dementia 2010. Alzheimers Dement 9(1–11):e3PubMedGoogle Scholar
  5. 5.
    Londong W, Barth H, Dammann HG, Hengels KJ, Kleinert R, Müller P, Rohde H, Simon B (1991) Dose-related healing of duodenal ulcer with the proton pump inhibitor lansoprazole. Aliment Pharmacol Ther 5:245–254PubMedCrossRefGoogle Scholar
  6. 6.
    Spechler SJ, Souza RF (2014) Barrett’s esophagus. N Engl J Med 371:836–845PubMedCrossRefGoogle Scholar
  7. 7.
    Tack J, Louis E, Persy V, Urbain D (2013) Optimal use of proton pump inhibitors for treating acid peptic diseases in primary care. Acta Gastroenterol Belg 6:393–402Google Scholar
  8. 8.
    Hollingworth S, Duncan EL, Martin JH (2010) Marked increase in proton pump inhibitors use in Australia. Pharmacoepidemiol Drug Saf 19:1019–1024PubMedCrossRefGoogle Scholar
  9. 9.
    Forgacs I, Loganayagam A (2008) Overprescribing proton pump inhibitors. BMJ 336:2–3PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Schwabe U, Paffrath D (eds) (2013) Arzneiverordnungs-Report 2013: Aktuelle Daten, Kosten, Trends und Kommentare. Springer, BerlinGoogle Scholar
  11. 11.
    Pasina L, Nobili A, Tettamanti M, Salerno F, Corrao S, Marengoni A, Iorio A, Marcucci M, Mannucci PM, REPOSI Investigators (2011) Prevalence and appropriateness of drug prescriptions for peptic ulcer and gastro-esophageal reflux disease in a cohort of hospitalized elderly. Eur J Intern Med 22:205–210PubMedCrossRefGoogle Scholar
  12. 12.
    Heidelbaugh JJ, Goldberg KL, Inadomi JM (2010) Magnitude and economic effect of overuse of antisecretory therapy in the ambulatory care setting. Am J Manag Care 16:e228–e234PubMedGoogle Scholar
  13. 13.
    Fireman Z, Kopelman Y, Sternberg A (1997) Central nervous system side effects after proton pump inhibitor treatment. J Clin Gastroenterol 25:718PubMedCrossRefGoogle Scholar
  14. 14.
    Lam JR, Schneider JL, Zhao W, Corley DA (2013) Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 310:2435–2442PubMedCrossRefGoogle Scholar
  15. 15.
    Badiola N, Alcalde V, Pujol A, Münter LM, Multhaup G, Lleó A, Coma M, Soler-López M, Aloy P (2013) The proton-pump inhibitor lansoprazole enhances amyloid beta production. PLoS One 8:e58837PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Vogiatzoglou A, Smith AD, Nurk E, Drevon CA, Ueland PM, Vollset SE, Nygaard HA, Engedal K, Tell GS, Refsum H (2013) Cognitive function in an elderly population: interaction between vitamin B12 status, depression, and apolipoprotein E ε4: the Hordaland Homocysteine Study. Psychosom Med 75:20–29PubMedCrossRefGoogle Scholar
  17. 17.
    Majumdar A, Cruz D, Asamoah N, Buxbaum A, Sohar I, Lobel P, Maxfield FR (2007) Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils. Mol Biol Cell 18:1490–1496PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Pillay CS, Elliott E, Dennison C (2002) Endolysosomal proteolysis and its regulation. Biochem J 363:417–429PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Mattsson JP, Väänänen K, Wallmark B, Lorentzon P (1991) Omeprazole and bafilomycin, two proton pump inhibitors: differentiation of their effects on gastric, kidney and bone H(+)-translocating ATPases. Biochim Biophys Acta 1065:261–268PubMedCrossRefGoogle Scholar
  20. 20.
    Fallahzadeh MK, Borhani Haghighi A, Namazi MR (2010) Proton pump inhibitors: predisposers to Alzheimer disease? J Clin Pharm Ther 35:125–126PubMedCrossRefGoogle Scholar
  21. 21.
    Tosto G, Reitz C (2013) Genome-wide association studies in Alzheimer’s disease: a review. Curr Neurol Neurosci Rep 13:381PubMedCrossRefGoogle Scholar
  22. 22.
    Jessen F, Wiese B, Bachmann C, Eifflaender-Gorfer S, Haller F, Kölsch H, Luck T, Mösch E, van den Bussche H, Wagner M, Wollny A, Zimmermann T, Pentzek M, Riedel-Heller SG, Romberg HP, Weyerer S, Kaduszkiewicz H, Maier W, Bickel H, German Study on Aging, Cognition and Dementia in Primary Care Patients Study Group (2010) Prediction of dementia by subjective memory impairment: effects of severity and temporal association with cognitive impairment. Arch Gen Psychiatry 67:414–422PubMedCrossRefGoogle Scholar
  23. 23.
    Jessen F, Wiese B, Bickel H, Eiffländer-Gorfer S, Fuchs A, Kaduszkiewicz H, Köhler M, Luck T, Mösch E, Pentzek M, Riedel-Heller SG, Wagner M, Weyerer S, Maier W, van den Bussche H; AgeCoDe Study Group (2011) Prediction of dementia in primary care patients. PLoS One 6:e16852CrossRefGoogle Scholar
  24. 24.
    Luck T, Riedel-Heller SG, Luppa M, Wiese B, Wollny A, Wagner M, Bickel H, Weyerer S, Pentzek M, Haller F, Moesch E, Werle J, Eisele M, Maier W, van den Bussche H, Kaduszkiewicz H, AgeCoDe Study Group (2010) Risk factors for incident mild cognitive impairment—results from the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe). Acta Psychiatr Scand 121:260–272PubMedCrossRefGoogle Scholar
  25. 25.
    Zaudig M, Hiller W (1996) SIDAM-Handbuch: Strukturiertes Interview für die Diagnose einer Demenz vom Alzheimer Typ, Multiinfarkt- (oder vaskulären) Demenz und Demenzen anderer Ätiologie nach DSM-III-R, DSM-IV und ICD-10. Huber, BernGoogle Scholar
  26. 26.
    Reisberg B, Ferris SH, de Leon MJ, Crook T (1982) The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry 139:1136–1139PubMedCrossRefGoogle Scholar
  27. 27.
    Blessed G, Tomlinson BE, Roth M (1968) The association between quantitative measures of dementia and of senile changes in the cerebral grey matter of elderly subjects. Br J Psychiatry 114:797–811PubMedCrossRefGoogle Scholar
  28. 28.
    Hixson JE, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 31:545–548PubMedGoogle Scholar
  29. 29.
    McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944PubMedCrossRefGoogle Scholar
  30. 30.
    Román GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A et al (1993) Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN International Workshop. Neurology 43:250–260PubMedCrossRefGoogle Scholar
  31. 31.
    König W, Lüttinger P, Müller W (1988) A comparative analysis of the development and structure of educational systems. Methodological foundations and the construction of a comparative education scale. CASMIN working paper no.12. University of MannheimGoogle Scholar
  32. 32.
    Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, Leirer VO (1983) Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 17:37–49CrossRefGoogle Scholar
  33. 33.
    Carnahan RM, Lund BC, Perry PJ, Pollock BG, Culp KR (2006) The Anticholinergic Drug Scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J Clin Pharmacol 46:1481–1486PubMedCrossRefGoogle Scholar
  34. 34.
    Hajjar ER, Cafiero AC, Hanlon JT (2007) Polypharmacy in elderly patients. Am J Geriatr Pharmacother 5:345–351PubMedCrossRefGoogle Scholar
  35. 35.
    Gnjidic D, Hilmer SN, Blyth FM, Naganathan V, Waite L, Seibel MJ, McLachlan AJ, Cumming RG, Handelsman DJ, Le Couteur DG (2012) Polypharmacy cutoff and outcomes: five or more medicines were used to identify community-dwelling older men at risk of different adverse outcomes. J Clin Epidemiol 65:989–995PubMedCrossRefGoogle Scholar
  36. 36.
    Khalili H, Huang ES, Jacobson BC, Camargo CA Jr, Feskanich D, Chan AT (2012) Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ 344:e372PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    de Jager CP, Wever PC, Gemen EF, van Oijen MG, van Gageldonk-Lafeber AB, Siersema PD, Kusters GC, Laheij RJ (2012) Proton pump inhibitor therapy predisposes to community-acquired Streptococcus pneumoniae pneumonia. Aliment Pharmacol Ther 36:941–949PubMedCrossRefGoogle Scholar
  38. 38.
    Reynolds E (2006) Vitamin B12, folic acid, and the nervous system. Lancet Neurol 5:949–960PubMedCrossRefGoogle Scholar
  39. 39.
    O’Leary F, Allman-Farinelli M, Samman S (2012) Vitamin B12 status, cognitive decline and dementia: a systematic review of prospective cohort studies. Br J Nutr 108:1948–1961PubMedCrossRefGoogle Scholar
  40. 40.
    Norman EJ, Morrison JA (1993) Screening elderly populations for cobalamin (vitamin B12) deficiency using the urinary methylmalonic acid assay by gas chromatography mass spectrometry. Am J Med 94:589–594PubMedCrossRefGoogle Scholar
  41. 41.
    Mirkazemi C, Peterson GM, Tenni PC, Jackson SL (2012) Vitamin B12 deficiency in Australian residential aged care facilities. J Nutr Health Aging 16:277–280PubMedCrossRefGoogle Scholar
  42. 42.
    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344PubMedCrossRefGoogle Scholar
  43. 43.
    Cheng FC, Ho YF, Hung LC, Chen CF, Tsai TH (2002) Determination and pharmacokinetic profile of omeprazole in rat blood, brain and bile by microdialysis and high-performance liquid chromatography. J Chromatogr A 949:35–42PubMedCrossRefGoogle Scholar
  44. 44.
    Rojo LE, Alzate-Morales J, Saavedra IN, Davies P, Maccioni RB (2010) Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer’s disease. J Alzheimers Dis 19:573–589PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Britta Haenisch
    • 1
    • 2
    • 3
  • Klaus von Holt
    • 1
  • Birgitt Wiese
    • 4
  • Jana Prokein
    • 4
  • Carolin Lange
    • 5
  • Annette Ernst
    • 5
  • Christian Brettschneider
    • 6
  • Hans-Helmut König
    • 6
  • Jochen Werle
    • 7
  • Siegfried Weyerer
    • 7
  • Melanie Luppa
    • 8
  • Steffi G. Riedel-Heller
    • 8
  • Angela Fuchs
    • 9
  • Michael Pentzek
    • 9
  • Dagmar Weeg
    • 10
  • Horst Bickel
    • 10
  • Karl Broich
    • 2
  • Frank Jessen
    • 1
    • 3
  • Wolfgang Maier
    • 1
    • 3
  • Martin Scherer
    • 5
  1. 1.German Center for Neurodegenerative Diseases (DZNE)BonnGermany
  2. 2.Federal Institute for Drugs and Medical Devices (BfArM)BonnGermany
  3. 3.Department of PsychiatryUniversity of BonnBonnGermany
  4. 4.Institute for General PracticeHannover Medical SchoolHannoverGermany
  5. 5.Department of Primary Medical CareUniversity Medical Center Hamburg-EppendorfHamburgGermany
  6. 6.Department of Health Economics and Health Services Research, Hamburg Center for Health EconomicsUniversity Medical Center Hamburg-EppendorfHamburgGermany
  7. 7.Central Institute of Mental HealthMedical Faculty Mannheim/Heidelberg UniversityMannheimGermany
  8. 8.Institute of Social Medicine, Occupational Health and Public HealthUniversity of LeipzigLeipzigGermany
  9. 9.Institute of General Practice (IFAM)Medical Faculty of the Heinrich-Heine-University DüsseldorfDüsseldorfGermany
  10. 10.Department of PsychiatryTechnical University of MunichMunichGermany

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