Neurological Sciences

, Volume 31, Issue 3, pp 321–325 | Cite as

Cytokine polymorphisms and Alzheimer disease: possible associations

  • G. Ribizzi
  • S. Fiordoro
  • S. Barocci
  • E. Ferrari
  • M. Megna
Original Article


Alzheimer’s disease (AD) is a degenerative dementia characterized by typical, destructive alterations of neurons (neurofibrillary tangles and amyloid plaques), and glial proliferation. Cytokine-driven inflammatory environment can contribute to the pathogenesis and/or progression of the disease. The aim of the study was to evaluate and compare genotypic and allelic polymorphisms of 13 cytokine genes in 19 Caucasoid AD patients with medium–high level of dementia (assessed by an MMSE < 24) and 20 normal controls affected by non inflammatory neuropsychiatric disease. Polymorphisms in the genes of IL-lA, IL-lB, IL-2, IL-4, IL-6, IL-10, IL-12, IFN-G, TGF-β, TNF-α, and of the cytokine receptors IL-lR, IL-IRA, IL-4RA were investigated. APO-E and ACE gene polymorphisms were carried out in the patient’s group only to evaluate a possible association with known genetic risk factors for AD. A highly significant presence of some alleles belonging to anti-inflammatory cytokine genes was found; particularly the C allele for the −590 promoter and T allele for the −1098 promoter of IL-4 appeared in a significantly higher percentage as compared with controls (P < 0.0006 and P < 0.0005, respectively), while a lesser significance was observed for the allele C of the −819 promoter of IL-10 (P < 0.03). Finally, in the group of demented patients for the APO-E gene we found a statistically significant presence of the E4 allele, whereas no difference was found for the polymorphisms of the ACE gene. Our observations corroborate the possible presence of a pro-inflammatory environment in AD patients, partly sustained by the low expression of anti-inflammatory cytokine genes when defined alleles are present. Large cohort studies are necessary in order to assess the real association of some cytokine alleles or haplotypes with AD.


Alzheimer Cytokine Genetic polymorphisms 


  1. 1.
    Steinman L (2008) Nuanced roles of cytokines in three major human brain disorders. J Clin Invest 118:3557–3563CrossRefPubMedGoogle Scholar
  2. 2.
    Lombardi VRM, Garcia M, Rey L, Cacabelos R (1999) Characterization of cytokine production, screening of lymphocyte subset patterns and in vitro apoptosis in healthy and Alzheimer’s Disease (AD) individuals. J Neuroimmunol 97:163–171CrossRefPubMedGoogle Scholar
  3. 3.
    Lopez OL, Rabin BS, Huff J, Rezek D, Reinmuth OM (1992) Serum autoantibodies in patients with Alzheimer’s Disease and vascular dementia and in nondemented control subjects. Stroke 23:1078–1083PubMedGoogle Scholar
  4. 4.
    Combarros O, Sanchez-Guerra M, Infante J, Llorca J, Berciano J (2002) Gene dose-dependent association of interleukin-1A (−889) allele 2 polymorphism with Alzheimer’s disease. J Neurol 249:1242–1245CrossRefPubMedGoogle Scholar
  5. 5.
    Nicoll JAR, Mrak RE, Graham DJ, Stewart J, Wilcock G, MacGowan S, Esiri MM, Murray LS, Dewar D, Love S, Moss T, Griggin WST (2000) Association of interleukin-1 gene polymorphisms in Alzheimer’s disease. Ann Neurol 47:365–368CrossRefPubMedGoogle Scholar
  6. 6.
    Licastro F, Pedrini S, Govoni M, Pession A, Ferri C, Annoni G, Casadei V, Veglia F, Bertolini S, Grimaldi LME (1999) Apolipoprotein E and α-1-antichymotrypsin allele polymorphism in sporadic and familial Alzheimer’s disease. Neurosci Lett 270:129–132CrossRefPubMedGoogle Scholar
  7. 7.
    Walzer DG, Lih-Fen L, Beach TG (2001) Gene expression profiling of amyloid beta peptide stimulated human post-mortem brain microglia. Neurobiol Aging 22:957–966CrossRefGoogle Scholar
  8. 8.
    Wang G, Zhang Y, Chen B, Cheng J (2003) Preliminary studies on Alzheimer’s disease using cDNA microarrays. Mech Ageing Dev 124:115–124CrossRefPubMedGoogle Scholar
  9. 9.
    Eikelenboom P, Bate C, Van Gool WA, Hoozemans JJM, Rozemuller JM, Veerhuis R, Williams A (2002) Neuroinflammation in Alzheimer’s disease and prion disease. Glia 40:232–239CrossRefPubMedGoogle Scholar
  10. 10.
    Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericack-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ et al (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472PubMedGoogle Scholar
  11. 11.
    Narain Y, Yip A, Murphy T, Brayne C, Easton D, Grimley Evans J, Xuereb J, Cairns N, Esiri MM, Furlong R, Rubinsztein ad (2000) The ACE gene and Alzheimer’s disease susceptibility. J Med Genet 37:695–697CrossRefPubMedGoogle Scholar
  12. 12.
    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(7):939–944PubMedGoogle Scholar
  13. 13.
    Uboldi de Capei MU, Dametto E, Fasano ME, Rendine S, Curtoni ES (2003) Genotyping for cytokine polymorphisms: allele frequencies in the Italian population. Eur J Immunogenet 30(1):5–10CrossRefPubMedGoogle Scholar
  14. 14.
    Laws SM, Hone E, Gandy S, Martins RN (2003) Expanding the association between the APOE gene and the risk of Alzheimer’s disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription. J Neurochem 84(6):1215–1236CrossRefPubMedGoogle Scholar
  15. 15.
    Barocci S, Ginevri F, Valente U, Torre F, Gusmano R, Nocera A (1999) Correlation between angiotensin-converting enzyme gene insertion/deletion polymorphism and kidney graft long-term outcome in pediatric recipients: a single-center analysis. Transplantation 67(4):534–538CrossRefPubMedGoogle Scholar
  16. 16.
    Ma SL, Tang NL, Lam LC, Chiu HF (2005) The association between promoter polymorphism of the interleukin-10 gene and Alzheimer’s disease. Neurobiol Aging 26(7):1005–1010CrossRefPubMedGoogle Scholar
  17. 17.
    Gervaziev YV, Kaznacheev VA, Gervazieva VB (2006) Allelic polymorphisms in the interleukin-4 promoter regions and their association with bronchial asthma among the Russian population. Int Arch Allergy Immunol 141(3):257–264CrossRefPubMedGoogle Scholar
  18. 18.
    Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW (1998) Interleukin 10 secretion in relation to human IL-10 locus haplotypes. PNAS 95(16):9465–9470CrossRefPubMedGoogle Scholar
  19. 19.
    Szczepanik AM, Funes S, Petko W, Ringheim GE (2001) IL-4, IL-10 and IL-13 modulate A beta(1–42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J Neuroimmunol 113(1):49–62CrossRefPubMedGoogle Scholar
  20. 20.
    Meda L, Baron P, Prat E, Scarpini E, Scarlato G, Cassatella MA, Rossi F (1999) Proinflammatory profile of cytokine production by human monocytes and murine microglia stimulated with beta-amyloid[25–35]. J Neuroimmunol 93(1–2):45–52CrossRefPubMedGoogle Scholar
  21. 21.
    Rosenwasser LJ, Klemm DJ, Dresback JK, Inamura H, Mascali JJ, Klinnert M, Borish L (1995) Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Allergy 25(Suppl 2):74–78CrossRefPubMedGoogle Scholar
  22. 22.
    Scassellati C, Zanardini R, Squitti R, Bocchio-Chiavetto L, Bonvicini C, Binetti G, Zanetti O, Cassetta E, Gennarelli M (2004) Promoter haplotypes of interleukin-10 gene and sporadic Alzheimer’s disease. Neurosci Lett 356(2):119–122CrossRefPubMedGoogle Scholar
  23. 23.
    Marsh DG, Neely JD, Breazeale DR, Ghosh B, Friedhoff LR, Schou C, Beaty TH (1995) Total serum IgE levels and chromosome 5q. Clin Exp Allergy 25(Suppl 2):79–83CrossRefPubMedGoogle Scholar
  24. 24.
    Noguchi E, Shibasaki M, Arinami T, Takeda K, Yokouchi Y, Kawashima T, Yanagi H, Matsui A, Hamaguchi H (1998) Association of asthma and the interleukin-4 promoter gene in Japanese. Clin Exp Allergy 28(4):449–453CrossRefPubMedGoogle Scholar
  25. 25.
    Arai N, Nomura D, Villaret D, DeWaal Malefijt R, Seiki M, Yoshida M, Minoshima S, Fukuyama R, Maekawa M, Kudoh J et al (1989) Complete nucleotide sequence of the chromosomal gene for human IL-4 and its expression. J Immunol 142(1):274–282PubMedGoogle Scholar
  26. 26.
    Cinek O, Vavrincová P, Striz I, Drevínek P, Sedláková P, Vavrinec J, Slavcev A (2004) Association of single nucleotide polymorphisms within cytokine genes with juvenile idiopathic arthritis in the Czech population. J Rheumatol 31(6):1206–1210PubMedGoogle Scholar
  27. 27.
    Infante J, Sanz C, Fernández-Luna JL, Llorca J, Berciano J, Combarros O (2004) Gene–gene interaction between interleukin-6 and interleukin-10 reduces AD risk. Neurology 63(6):1135–1136PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • G. Ribizzi
    • 1
  • S. Fiordoro
    • 2
  • S. Barocci
    • 2
  • E. Ferrari
    • 2
  • M. Megna
    • 3
  1. 1.Department of NeurologyOspedale S. MartinoGenoaItaly
  2. 2.Immunology ServiceOspedale S. MartinoGenoaItaly
  3. 3.Department of NeurologyUniversity of BariBariItaly

Personalised recommendations