CNS Drugs

, Volume 30, Issue 11, pp 1111–1120 | Cite as

Treatment for Rheumatoid Arthritis and Risk of Alzheimer’s Disease: A Nested Case-Control Analysis

  • Richard C. ChouEmail author
  • Michael Kane
  • Sanjay Ghimire
  • Shiva Gautam
  • Jiang Gui
Original Research Article



It is increasingly becoming accepted that inflammation may play an important role in the pathogenesis of Alzheimer’s disease (AD), as several immune-related genes have been associated with AD. Among these is tumor necrosis factor (TNF)-α, a proinflammatory cytokine known to play an important role in autoimmune disorders, including rheumatoid arthritis (RA). Although AD and RA appear to involve similar pathological mechanisms through the production of TNF-α, the relationship between AD and RA remains unknown.


To determine the relative risk of AD among RA patients and non-RA patients, and whether anti-TNF therapy for RA was associated with a lower risk of AD in RA patients.


We performed a nested case-control study of more than 8.5 million commercially insured adults (aged ≥18 years) in all 50 US states, Puerto Rico, and US Virgin Islands in the Verisk Health claims database. We derived a sub-cohort of subjects with a diagnosis of RA (controls), or RA and AD (cases), matching cases and controls based on age, sex, exposure assessment period, and methotrexate treatment. We also assessed relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab. Odds ratios were adjusted for comorbidities, including coronary artery disease, diabetes mellitus, and peripheral vascular disease.


AD was more prevalent (p < 0.0001) among RA patients (0.79 %) than among those without RA (0.11 %). Chronic conditions such as coronary artery disease (odds ratio [OR] 1.48; 95 % confidence interval [CI] 1.04–2.05; p = 0.03), diabetes (OR 1.86; 95 % CI 1.32–2.62; p = 0.0004), and peripheral vascular disease (OR 1.61; 95 % CI 1.06–2.43; p = 0.02) significantly increased the relative risk of AD among RA patients. Exposure to anti-TNF agents as a class, but not other immunosuppressive drugs studied, was associated with lowered risk of AD among RA patients (unadjusted OR 0.44; 95 % CI 0.22–0.87; p = 0.02; adjusted OR 0.45; 95 % CI 0.23–0.90; p = 0.02). Sub-group analysis demonstrated that of the three anti-TNF agents studied, only etanercept (unadjusted OR, 0.33; 95 % CI 0.08–0.94; p = 0.03; adjusted OR 0.30; 95 % CI 0.08–0.89; p = 0.02) was associated with a decreased risk of AD in RA patients.


There is an increased risk of AD in the studied RA population. The relative risk of AD among RA subjects was lowered in those exposed to etanercept. Anti-TNF therapy with etanercept shows promise as a potential treatment for AD.


Rheumatoid Arthritis Infliximab Rheumatoid Arthritis Patient Etanercept Adalimumab 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Compliance with Ethical Standards


This work was partially supported by Grant No. UL1 RR025758–Harvard Clinical and Translational Science Center, from the National Center for Research Resources for Shiva Gautam.

Conflict of interest

Richard C. Chou, Michael Kane, Sanjay Ghimire, and Jiang Gui have no conflicts of interest to declare. Shiva Gautam was partially supported by the aforementioned grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the article.

Ethical approval

Analysis of de-identified data was exempted from continuing review by the Committee for the Protection of Human Subjects at Dartmouth College and Beth Israel Deaconess Medical Center Committee on Clinical Investigation.

Supplementary material

40263_2016_374_MOESM1_ESM.pdf (147 kb)
Supplementary material 1 (PDF 146 kb)


  1. 1.
    Alzheimer's Association. 2015 Alzheimer’s disease facts and figures. Alzheimers Dement. 2015;11(3):332–84.CrossRefGoogle Scholar
  2. 2.
    Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology. 2013;80(19):1778–83. doi: 10.1212/WNL.0b013e31828726f5.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Qiu C, De Ronchi D, Fratiglioni L. The epidemiology of the dementias: an update. Curr Opin Psychiatry. 2007;20(4):380–5. doi: 10.1097/YCO.0b013e32816ebc7b.PubMedCrossRefGoogle Scholar
  4. 4.
    Mayeux R, Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2(8). doi: 10.1101/cshperspect.a006239.
  5. 5.
    Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45(12):1452–8. doi: 10.1038/ng.2802.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015;16(6):358–72. doi: 10.1038/nrn3880.PubMedCrossRefGoogle Scholar
  7. 7.
    Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat. 1995;8(6):429–31. doi: 10.1002/ca.980080612.PubMedCrossRefGoogle Scholar
  8. 8.
    Beljahow S. Pathological changes in the brain in dementia senilis. J Ment Sci. 1889;35:261–2.Google Scholar
  9. 9.
    Simchowicz T. Sur la signification des plaques seniles et sur la formule senile de l`ecorce cerebrale. Rev Neurol. 1924;31:221–7.Google Scholar
  10. 10.
    Gu L, Guo Z. Alzheimer’s Abeta42 and Abeta40 peptides form interlaced amyloid fibrils. J Neurochem. 2013;126(3):305–11. doi: 10.1111/jnc.12202.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Gravina SA, Ho L, Eckman CB, Long KE, Otvos L Jr, Younkin LH, et al. Amyloid beta protein (A beta) in Alzheimer’s disease brain: biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42(43). J Biol Chem. 1995;270(13):7013–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Younkin SG. Evidence that A beta 42 is the real culprit in Alzheimer’s disease. Ann Neurol. 1995;37(3):287–8. doi: 10.1002/ana.410370303.PubMedCrossRefGoogle Scholar
  13. 13.
    Buckholtz NS. Perspective: in search of biomarkers. Nature. 2011;475(7355):S8. doi: 10.1038/475S8a.PubMedCrossRefGoogle Scholar
  14. 14.
    Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. Lancet. 2016;. doi: 10.1016/S0140-6736(15)01124-1.Google Scholar
  15. 15.
    McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263–9. doi: 10.1016/j.jalz.2011.03.005.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):270–9. doi: 10.1016/j.jalz.2011.03.008.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280–92. doi: 10.1016/j.jalz.2011.03.003.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Tarkowski E, Blennow K, Wallin A, Tarkowski A. Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol. 1999;19(4):223–30.PubMedCrossRefGoogle Scholar
  19. 19.
    Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Pychiatry. 2003;74(9):1200–5.CrossRefGoogle Scholar
  20. 20.
    Brosseron F, Krauthausen M, Kummer M, Heneka MT. Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: a comparative overview. Mol Neurobiol. 2014;50(2):534–44. doi: 10.1007/s12035-014-8657-1.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, et al. Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med. 2007;13(11):1359–62. doi: 10.1038/nm1653.PubMedCrossRefGoogle Scholar
  22. 22.
    Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009;73(10):768–74. doi: 10.1212/WNL.0b013e3181b6bb95.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest. 2008;118(11):3537–45. doi: 10.1172/JCI36389.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. New Engl J Med. 2011;365(23):2205–19. doi: 10.1056/NEJMra100496510.7748/phc2011. Scholar
  25. 25.
    McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis: shaping the immunological landscape. Nat Rev Rheumatol. 2016;12(1):63–8. doi: 10.1038/nrrheum.2015.171.PubMedCrossRefGoogle Scholar
  26. 26.
    Cunnane G. Amyloid precursors and amyloidosis in inflammatory arthritis. Curr Opin Rheumatol. 2001;13(1):67–73.PubMedCrossRefGoogle Scholar
  27. 27.
    Westermark GT, Fandrich M, Westermark P. AA amyloidosis: pathogenesis and targeted therapy. Ann Rev Pathol. 2015;10:321–44. doi: 10.1146/annurev-pathol-020712-163913.CrossRefGoogle Scholar
  28. 28.
    Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997;337(13):898–909. doi: 10.1056/NEJM199709253371306.PubMedCrossRefGoogle Scholar
  29. 29.
    Corrao G, Zambon A, Faini S, Bagnardi V, Leoni O, Suissa S. Short-acting inhaled beta-2-agonists increased the mortality from chronic obstructive pulmonary disease in observational designs. J Clin Epidemiol. 2005;58(1):92–7. doi: 10.1016/j.jclinepi.2004.04.013.PubMedCrossRefGoogle Scholar
  30. 30.
    Bernatsky S, Hudson M, Suissa S. Anti-rheumatic drug use and risk of serious infections in rheumatoid arthritis. Rheumatology (Oxford). 2007;46(7):1157–60. doi: 10.1093/rheumatology/kem076.PubMedCrossRefGoogle Scholar
  31. 31.
    Rose S, Laan MJ. Why match? Investigating matched case-control study designs with causal effect estimation. Int J Biostat. 2009;5(1):Article 1. doi: 10.2202/1557-4679.1127.
  32. 32.
    McInnes IB, O’Dell JR. State-of-the-art: rheumatoid arthritis. Ann Rheum Dis. 2010;69(11):1898–906. doi: 10.1136/ard.2010.134684.PubMedCrossRefGoogle Scholar
  33. 33.
    Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part I. Arthritis Rheum. 2008;58(1):15–25. doi: 10.1002/art.23177.PubMedCrossRefGoogle Scholar
  34. 34.
    Tobon GJ, Youinou P, Saraux A. The environment, geo-epidemiology, and autoimmune disease: eheumatoid arthritis. J Autoimmun. 2010;35(1):10–4. doi: 10.1016/j.jaut.2009.12.009.PubMedCrossRefGoogle Scholar
  35. 35.
    Appenzeller S, Bertolo MB, Costallat LT. Cognitive impairment in rheumatoid arthritis. Methods Find Exp Clin Pharmacol. 2004;26(5):339–43.PubMedCrossRefGoogle Scholar
  36. 36.
    Mattsson N, Tosun D, Insel PS, Simonson A, Jack CR Jr, Beckett LA, et al. Association of brain amyloid-beta with cerebral perfusion and structure in Alzheimer’s disease and mild cognitive impairment. Brain. 2014;137(Pt 5):1550–61. doi: 10.1093/brain/awu043.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Beeri MS, Rapp M, Silverman JM, Schmeidler J, Grossman HT, Fallon JT, et al. Coronary artery disease is associated with Alzheimer disease neuropathology in APOE4 carriers. Neurology. 2006;66(9):1399–404. doi: 10.1212/01.wnl.0000210447.19748.0b.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, et al. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology. 2010;75(13):1195–202. doi: 10.1212/WNL.0b013e3181f4d7f8.PubMedCrossRefGoogle Scholar
  39. 39.
    Tetta C, Camussi G, Modena V, Di Vittorio C, Baglioni C. Tumour necrosis factor in serum and synovial fluid of patients with active and severe rheumatoid arthritis. Ann Rheum Dis. 1990;49(9):665–7.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Centola M, Cavet G, Shen Y, Ramanujan S, Knowlton N, Swan KA, et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One. 2013;8(4):e60635. doi: 10.1371/journal.pone.0060635.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Tedde A, Putignano AL, Nacmias B, Bagnoli S, Cellini E, Sorbi S. Lack of association between TNF-alpha polymorphisms and Alzheimer’s disease in an Italian cohort. Neurosci Lett. 2008;446(2–3):139–42. doi: 10.1016/j.neulet.2008.09.044.PubMedCrossRefGoogle Scholar
  42. 42.
    Chen YM, Chen HH, Lan JL, Chen DY. Improvement of cognition, a potential benefit of anti-TNF therapy in elderly patients with rheumatoid arthritis. Jt Bone Spine. 2010;77(4):366–7. doi: 10.1016/j.jbspin.2010.01.017.CrossRefGoogle Scholar
  43. 43.
    Tweedie D, Sambamurti K, Greig NH. TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets. Curr Alzheimer Res. 2007;4(4):378–85.PubMedCrossRefGoogle Scholar
  44. 44.
    Mukhtyar C, Luqmani R. Current state of tumour necrosis factor {alpha} blockade in Wegener’s granulomatosis. Ann Rheum Dis. 2005;64 Suppl 4:iv31–6. doi: 10.1136/ard.2005.042416.
  45. 45.
    Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease: Crohn’s Disease cA2 Study Group. N Engl J Med. 1997;337(15):1029–35. doi: 10.1056/NEJM199710093371502.PubMedCrossRefGoogle Scholar
  46. 46.
    Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med. 2005;352(4):351–61. doi: 10.1056/NEJMoa041884.CrossRefGoogle Scholar
  47. 47.
    Baert FJ, D’Haens GR, Peeters M, Hiele MI, Schaible TF, Shealy D, et al. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn’s ileocolitis. Gastroenterology. 1999;116(1):22–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Kaymakcalan Z, Sakorafas P, Bose S, Scesney S, Xiong L, Hanzatian DK, et al. Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor. Clin Immunol. 2009;131(2):308–16. doi: 10.1016/j.clim.2009.01.002.PubMedCrossRefGoogle Scholar
  49. 49.
    Mpofu S, Fatima F, Moots RJ. Anti-TNF-alpha therapies: they are all the same (aren’t they?). Rheumatology (Oxford). 2005;44(3):271–3. doi: 10.1093/rheumatology/keh483.PubMedCrossRefGoogle Scholar
  50. 50.
    Butchart J, Brook L, Hopkins V, Teeling J, Puntener U, Culliford D, et al. Etanercept in Alzheimer disease: a randomized, placebo-controlled, double-blind, phase 2 trial. Neurology. 2015;84(21):2161–8. doi: 10.1212/WNL.0000000000001617.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Richard C. Chou
    • 1
    • 2
    Email author
  • Michael Kane
    • 3
    • 4
  • Sanjay Ghimire
    • 5
  • Shiva Gautam
    • 4
    • 6
  • Jiang Gui
    • 7
    • 8
    • 9
  1. 1.Section of RheumatologyDartmouth-Hitchcock Medical CenterLebanonUSA
  2. 2.Department of MedicineGeisel School of Medicine at DartmouthLebanonUSA
  3. 3.Division of RheumatologyMassachusetts General HospitalBostonUSA
  4. 4.Department of MedicineHarvard Medical SchoolBostonUSA
  5. 5.Verisk HealthWalthamUSA
  6. 6.Harvard CTSC Biostatistics ProgramBeth Israel Deaconess Medical CenterBostonUSA
  7. 7.Department of Biomedical Data ScienceGeisel School of Medicine at DartmouthLebanonUSA
  8. 8.Department of Community and Family MedicineGeisel School of Medicine at DartmouthLebanonUSA
  9. 9.The Dartmouth Institute for Health Policy and Clinical PracticeLebanonUSA

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