Skip to main content
Springer Nature Link
Log in

Non-Steroidal Anti-Inflammatory Drugs as a Treatment for Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Treatment Effect

  • Systematic Review
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Introduction

Alzheimer’s disease (AD) is the cause of more than two-thirds of all dementia cases. Although there is no effective treatment against this disorder, its association with neuroinflammation suggests that non-steroidal anti-inflammatory drugs (NSAIDs) might represent a potential therapeutic option.

Objective

The objective of this study was to evaluate the efficacy of NSAIDs in the treatment of AD using a meta-analysis approach.

Methods

MEDLINE, Web of Science, Science Direct, and the Cochrane Library were used to search all the randomized controlled trials that have evaluated the efficacy of NSAIDs as a treatment for AD (up to 1 October 2014). The overall effect of NSAIDs versus placebo was determined using a random effects model meta-analysis where we compared changes (i.e., mean differences pre- vs. post-treatment) between the two conditions in test scores indicative of cognition, disease severity, and related outcomes.

Results

Seven studies were finally included in the meta-analysis. Diclofenac/misoprostol, nimesulide, naproxen, rofecoxib, ibuprofen, indomethacin, tarenflurbil, and celecoxib were the NSAIDs used in these reports. The results of the AD Assessment Scale–cognitive subscale (ADAS–cog), the Clinical Dementia Rating Scale sum-of-boxes (CDR-SOB), and the Mini-Mental State Examination (MMSE) showed no statistical or clinical significance of NSAIDs treatment compared with placebo, i.e., mean differences of −0.24 (95 % Confidence Interval (CI) −1.04 to 0.57; P = 0.52), −0.07 (95 % CI −0.7 to 0.56; P = 0.82), and 0.35 (95 % CI −0.34 to 1.04; P = 0.32), respectively.

Conclusion

Current preliminary evidence suggests no beneficial effect of NSAIDs on cognition or overall AD severity. Thus, although more research is needed in the field, the evidence available does not support the use of NSAIDs for AD treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
€34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  1. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology. 1996;47(2):425–32.

    Article  CAS  PubMed  Google Scholar 

  2. Gomez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol. 1997;41(1):17–24.

    Article  CAS  PubMed  Google Scholar 

  3. Golde TE. Inflammation takes on Alzheimer disease. Nat Med. 2002;8(9):936–8.

    Article  CAS  PubMed  Google Scholar 

  4. Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S, et al. Inflammatory components in human Alzheimer’s disease and after active amyloid-beta42 immunization. Brain. 2013;136(Pt 9):2677–96.

    Article  PubMed  Google Scholar 

  5. Eikelenboom P, van Gool WA. Neuroinflammatory perspectives on the two faces of Alzheimer’s disease. J Neural Transm. 2004;111(3):281–94.

    Article  CAS  PubMed  Google Scholar 

  6. Zhu X, Lee HG, Perry G, Smith MA. Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta. 2007;1772(4):494–502.

    Article  CAS  PubMed  Google Scholar 

  7. Yip AG, Green RC, Huyck M, Cupples LA, Farrer LA, Mirage Study Group. Nonsteroidal anti-inflammatory drug use and Alzheimer’s disease risk: the MIRAGE study. BMC Geriatr. 2005;5:2.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Szekely CA, Thorne JE, Zandi PP, Ek M, Messias E, Breitner JC, et al. Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer’s disease: a systematic review. Neuroepidemiology. 2004;23(4):159–69.

    Article  PubMed  Google Scholar 

  9. Thal LJ. Anti-inflammatory drugs and Alzheimer’s disease. Neurobiol Aging. 2000;21(3):449–50 (discussion 51–3).

    Article  CAS  PubMed  Google Scholar 

  10. Kolibas E, Korinkova V, Novotny V, Vajdickova K, Hunakova D. ADAS–cog (Alzheimer’s Disease Assessment Scale–cognitive subscale)—validation of the Slovak version. Bratisl Lek Listy. 2000;101(11):598–602.

    CAS  PubMed  Google Scholar 

  11. Tschanz JT, Corcoran CD, Schwartz S, Treiber K, Green RC, Norton MC, et al. Progression of cognitive, functional, and neuropsychiatric symptom domains in a population cohort with Alzheimer dementia: the Cache County Dementia Progression study. Am J Geriatr Psychiatry. 2011;19(6):532–42.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Hamrick I, Hafiz R, Cummings DM. Use of days of the week in a modified mini-mental state exam (M-MMSE) for detecting geriatric cognitive impairment. J Am Board Fam Med. 2013;26(4):429–35.

    Article  PubMed  Google Scholar 

  13. Bax L, Yu LM, Ikeda N, Tsuruta H, Moons KG. Development and validation of MIX: comprehensive free software for meta-analysis of causal research data. BMC Med Res Methodol. 2006;6:50.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Babiloni C, Frisoni GB, Del Percio C, Zanetti O, Bonomini C, Cassetta E, et al. Ibuprofen treatment modifies cortical sources of EEG rhythms in mild Alzheimer’s disease. Clin Neurophysiol. 2009;120(4):709–18.

    Article  CAS  PubMed  Google Scholar 

  15. Scharf S, Mander A, Ugoni A, Vajda F, Christophidis N. A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease. Neurology. 1999;53(1):197–201.

    Article  CAS  PubMed  Google Scholar 

  16. Aisen PS, Schmeidler J, Pasinetti GM. Randomized pilot study of nimesulide treatment in Alzheimer’s disease. Neurology. 2002;58(7):1050–4.

    Article  CAS  PubMed  Google Scholar 

  17. Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003;289(21):2819–26.

    Article  CAS  PubMed  Google Scholar 

  18. Pasqualetti P, Bonomini C, Dal Forno G, Paulon L, Sinforiani E, Marra C, et al. A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer’s disease. Aging Clin Exp Res. 2009;21(2):102–10.

    Article  CAS  PubMed  Google Scholar 

  19. de Jong D, Jansen R, Hoefnagels W, Jellesma-Eggenkamp M, Verbeek M, Borm G, et al. No effect of one-year treatment with indomethacin on Alzheimer’s disease progression: a randomized controlled trial. PloS One. 2008;3(1):e1475.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, et al. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomised phase II trial. Lancet Neurol. 2008;7(6):483–93.

    Article  CAS  PubMed  Google Scholar 

  21. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009;302(23):2557–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Soininen H, West C, Robbins J, Niculescu L. Long-term efficacy and safety of celecoxib in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2007;23(1):8–21.

    Article  CAS  PubMed  Google Scholar 

  23. Reines SA, Block GA, Morris JC, Liu G, Nessly ML, Lines CR, et al. Rofecoxib: no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study. Neurology. 2004;62(1):66–71.

    Article  CAS  PubMed  Google Scholar 

  24. Rogers J, Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW, et al. Clinical trial of indomethacin in Alzheimer’s disease. Neurology. 1993;43(8):1609–11.

    Article  CAS  PubMed  Google Scholar 

  25. Sedwick P. Clinical significance versus statistical significance. BMJ. 2014;349(2130).

  26. Yu F, Kolanowski AM, Strumpf NE, Eslinger PJ. Improving cognition and function through exercise intervention in Alzheimer’s disease. J Nurs Scholarsh. 2006;38(4):358–65.

    Article  PubMed  Google Scholar 

  27. Andersen CK, Wittrup-Jensen KU, Lolk A, Andersen K, Kragh-Sorensen P. Ability to perform activities of daily living is the main factor affecting quality of life in patients with dementia. Health Qual Life outcomes. 2004;2:52.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Andrieu S, Reynish E, Nourhashemi F, Shakespeare A, Moulias S, Ousset PJ, et al. Predictive factors of acute hospitalization in 134 patients with Alzheimer’s disease: a one year prospective study. Int J Geriatr psychiatry. 2002;17(5):422–6.

    Article  PubMed  Google Scholar 

  29. Steeman E, Abraham IL, Godderis J. Risk profiles for institutionalization in a cohort of elderly people with dementia or depression. Arch Psychiatr Nurs. 1997;11(6):295–303.

    Article  CAS  PubMed  Google Scholar 

  30. Newcomer R, Covinsky KE, Clay T, Yaffe K. Predicting 12-month mortality for persons with dementia. J Gerontol B Psychol Sci Soc Sci. 2003;58(3):S187–98.

    Article  PubMed  Google Scholar 

  31. Glass GV, McGraw B, Smith ML. Meta-analysis in social sciences. Beverly Hills: Sage; 1984.

    Google Scholar 

  32. Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies. BMJ. 2003;327(7407):128.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Breitner JC, Zandi PP. Do nonsteroidal antiinflammatory drugs reduce the risk of Alzheimer’s disease? N Engl J Med. 2001;345(21):1567–8.

    Article  CAS  PubMed  Google Scholar 

  34. Kalaria RN. Microglia and Alzheimer’s disease. Curr Opin Hematol. 1999;6(1):15–24.

    Article  CAS  PubMed  Google Scholar 

  35. Gorlovoy P, Larionov S, Pham TT, Neumann H. Accumulation of tau induced in neurites by microglial proinflammatory mediators. FASEB J. 2009;23(8):2502–13.

    Article  CAS  PubMed  Google Scholar 

  36. Benzing WC, Wujek JR, Ward EK, Shaffer D, Ashe KH, Younkin SG, et al. Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice. Neurobiol Aging. 1999;20(6):581–9.

    Article  CAS  PubMed  Google Scholar 

  37. Aisen PS. The potential of anti-inflammatory drugs for the treatment of Alzheimer’s disease. Lancet Neurol. 2002;1(5):279–84.

    Article  CAS  PubMed  Google Scholar 

  38. Tuppo EE, Arias HR. The role of inflammation in Alzheimer’s disease. Int J Biochem Cell Biol. 2005;37(2):289–305.

    Article  CAS  PubMed  Google Scholar 

  39. Rabinovici GD, Jagust WJ. Amyloid imaging in aging and dementia: testing the amyloid hypothesis in vivo. Behav Neurol. 2009;21(1):117–28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Shohamy D, Turk-Browne NB. Mechanisms for widespread hippocampal involvement in cognition. J Exp Psychol Gen. 2013;142(4):1159–70.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Stewart WF, Kawas C, Corrada M, Metter EJ. Risk of Alzheimer’s disease and duration of NSAID use. Neurology. 1997;48(3):626–32.

    Article  CAS  PubMed  Google Scholar 

  42. Hawkey CJ, Lanas AI, Sardinia NM. Doubt and certainty about nonsteroidal anti-inflammatory drugs in the year 2000: a multidisciplinary expert statement. Am J Med. 2001;110(1A):79S–100S.

    Article  CAS  PubMed  Google Scholar 

  43. Hawkey CJ. COX-2 inhibitors. Lancet. 1999;353(9149):307–14.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

All the authors (Marina Miguel-Álvarez, Alejandro Santos-Lozano, Fabian Sanchis-Gomar, Helios Pareja-Galeano, Carmen Fiuza-Luces, Nuria Garatachea, and Alejandro Lucia) declare they have no conflict of interest.

Funding

The authors received no funding to conduct this meta-analysis.

Author information

Authors and Affiliations

  1. Faculty of Health Science, Ponferrada Campus, University of León, Avenida de Astorga s/n, 24400, Ponferrada, León, Spain

    Marina Miguel-Álvarez & Alejandro Santos-Lozano

  2. Research Institute of Hospital 12 de Octubre (“i+12”), Madrid, Spain

    Alejandro Santos-Lozano, Carmen Fiuza-Luces, Helios Pareja-Galeano, Nuria Garatachea & Alejandro Lucia

  3. Department of Physiology, University of Valencia and Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain

    Fabian Sanchis-Gomar

  4. European University, Madrid, Spain

    Helios Pareja-Galeano & Alejandro Lucia

  5. Department of Physiotherapy and Nursing, University of Zaragoza, Huesca, Spain

    Nuria Garatachea

  6. GENUD (Growth, Exercise, Nutrition and Development) Research Group, University of Zaragoza, Zaragoza, Spain

    Nuria Garatachea

Authors
  1. Marina Miguel-Álvarez
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Alejandro Santos-Lozano
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Fabian Sanchis-Gomar
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Carmen Fiuza-Luces
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Helios Pareja-Galeano
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Nuria Garatachea
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Alejandro Lucia
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Alejandro Santos-Lozano.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (JPEG 709 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miguel-Álvarez, M., Santos-Lozano, A., Sanchis-Gomar, F. et al. Non-Steroidal Anti-Inflammatory Drugs as a Treatment for Alzheimer’s Disease: A Systematic Review and Meta-Analysis of Treatment Effect. Drugs Aging 32, 139–147 (2015). https://doi.org/10.1007/s40266-015-0239-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40266-015-0239-z

Keywords