, Volume 34, Issue 5, pp 1295–1308 | Cite as

The association between systemic inflammation and cognitive performance in the elderly: the Sydney Memory and Ageing Study

  • Julian N. TrollorEmail author
  • Evelyn Smith
  • Emmeline Agars
  • Stacey A. Kuan
  • Bernhard T. Baune
  • Lesley Campbell
  • Katherine Samaras
  • John Crawford
  • Ora Lux
  • Nicole A. Kochan
  • Henry Brodaty
  • Perminder Sachdev


Inflammation may contribute to cognitive decline and dementia. This study examined the cross-sectional relationships between markers of systemic inflammation (C-reactive protein, interleukins-1β, -6, -8, -10, -12, plasminogen activator inhibitor, serum amyloid A, tumour necrosis factor-α and vascular adhesion molecule-1) and cognitive function in 873 non-demented community-dwelling elderly participants aged 70–90 years. Regression analyses were performed to determine the relationships between cognitive domains and inflammatory markers, controlling for age, sex, education, cardiovascular risk factors, obesity and other metabolic factors, smoking, alcohol consumption, depression and presence of the apolipoprotein ε4 genotype. Regression analyses were repeated using four factors derived from a factor analysis of the cognitive tests. After Bonferroni correction for multiple testing, associations remained between raised levels of interleukin-12 and reduced performance in processing speed. Marked sex differences were noted in the abovementioned findings, with only females being significantly affected. Using the four factors derived from the factor analyses of cognitive test as dependent variables, interleukins-12 and -6 were both associated with the processing speed/executive function factor, even after controlling for relevant confounding factors. Thus, markers of systemic inflammation are related to cognitive deficits in a non-clinical community-dwelling elderly population, independent of depression, cardiovascular or metabolic risk factors, or presence of apolipoprotein ε4 genotype. Additional research is required to elucidate the pathophysiology and longitudinal development of these relationships.


Inflammation Ageing Cytokines Inflammaging Cognition Dementia 



This study was supported by a Dementia Research Grant through the Australian National Health and Medical Research Council (Grant ID 510124).

The Sydney MAS is supported by the Australian National Health and Medical Research Council Program Grant (Grant ID 350833). The authors wish to acknowledge the contributions of Brain and Ageing Research Program Staff especially Kristan Kang, Simone Reppermund and Melissa Slavin as well all MAS participants.

DNA was extracted by Genetic Repositories Australia, which is supported by an Australian National Health and Medical Research Council Grant (grant ID 401184). Arezoo Assareh and Karen Mather undertook the APOE genotyping in the laboratory of Peter Schofield and John Kwok at Neuroscience Research Australia.

We would also like to acknowledge and thank the accredited laboratory SEALS for their contribution.


  1. Alley DE, Crimmins EM, Karlamangla A, Hu P, Seeman TE (2008) Inflammation and rate of cognitive change in high-functioning older adults. J Gerontol 63A(1):50–55Google Scholar
  2. Alvarez A, Cacabelos R, Sanpedro C, Garcia-Fantini M, Aleixandre M (2007) Serum TNF-α levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging 28:533–536PubMedCrossRefGoogle Scholar
  3. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington DC, International VersionGoogle Scholar
  4. Anderson TM, Trollor JN, Sachdev PS, Brodaty H (2007) Effects of sociodemographic and health variables on Mini-Mental State Exam scores in older Australians. Am J Geriatr Psychiatry 15:467–476PubMedCrossRefGoogle Scholar
  5. Azad NA, Al Bugami M, Loy-English I (2007) Gender differences in dementia risk factors. Gend Med 4:120–129PubMedCrossRefGoogle Scholar
  6. Bagnoli S, Celline E, Tede A, Nacmias B, Piacentini S, Bessi V, Bracco L, Sorbi S (2007) Association of IL-10 promoter polymorphism in Italian Alzeimer's disease. Neurosci Lett 418:262–265PubMedCrossRefGoogle Scholar
  7. Baune BT, Ponath G, Golledge J, Varga G, Arolt V, Rothermundt M, Berger K (2008) Association between IL-8 cytokine and cognitive performance in an elderly general population – The MEMO-Study. Neurobiol Aging 29:937–944PubMedCrossRefGoogle Scholar
  8. Benton AL (1967) Problems of test construction in the field of aphasia. Cortex 3:32–58Google Scholar
  9. Benton Sivan AB, Spreen O (1996) Der Benton Test, 7th edn. Huber, BernGoogle Scholar
  10. Bermejo P, Martin-Aragon S, Benedi J, Susin C, Felici E, Gil P, Ribera JM et al (2008) Differences of peripheral inflammatory markers between mild cognitive impairment and Alzheimer's disease. Immunol Lett 117:198–202PubMedCrossRefGoogle Scholar
  11. Blom G (1958) Statistical estimates and transformed beta-variables. John Wiley and Sons, New YorkGoogle Scholar
  12. Bruunsgaard H, Andersen-Ranberg K, Jeune B, Pedersen AN, Skinhoj P, Pedersen BK (1999) A high plasma concentration of TNF-α is associated with dementia in centenarians. J Gerontol 54A(7):357–364Google Scholar
  13. Buckner RL (2004) Memory and executive function in aging and AD: multiple factors that cause decline and reserve factors that compensate. Neuron 44:195–208PubMedCrossRefGoogle Scholar
  14. Christensen H, Batterham PJ, Mackinnon AJ, Jorm AF, Mack HA et al (2008) The association of APOE genotype and cognitive decline in interaction with risk factors in a 65–69 year old community sample. BMC Geriatr 8:14PubMedCrossRefGoogle Scholar
  15. Danesh J et al (2000) Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ 321:199–204PubMedCrossRefGoogle Scholar
  16. Deniz-Naranjo MC, Munoz-Fernandez C, Alemany-Rodriguez MJ, Perez-Vieitez MC, Aladro-Benito Y, Irurita-Latasa J, Sanchez-Garcia F (2008) Cytokine IL-1 beta but not IL-1 alpha promoter polymorphism is associated with Alzheimer disease in a population from the Canary Islands, Spain. Eur J Neurol 15:1080–1084PubMedCrossRefGoogle Scholar
  17. Dik MG, Jonker C, Hack CE, Smit JH, Comijs HC, Eikelenboom P (2005) Serum inflammatory proteins and cognitive decline in older persons. Neurology 64:1371–1377PubMedCrossRefGoogle Scholar
  18. Dimopoulos N, Piperi C, Salonicioti A, Mitropoulos P, Kallai E, Liappas I et al (2006) Indicies of low-grade chronic inflammation correlate with early cognitive deterioration in an elderly Greek population. Neurosci Lett 398:118–123PubMedCrossRefGoogle Scholar
  19. Engelhart M, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC, Stijnen T, Hofman A, Witteman JCM, Breteler MMB (2004) Inflammatory proteins in plasma and the risk of dementia. Arch Neurol 61:668–672PubMedCrossRefGoogle Scholar
  20. Fastenau PS, Denburg NL, Mauer BA (1998) Parallel short forms for the Boston Naming Test: psychometric properties and norms for older adults. J Clin Exp Neuropsychol 20(6):828–834PubMedCrossRefGoogle Scholar
  21. Fischer P, Zehetmayer S, Bauer K, Huber K, Jungwirth S, Tragl KH (2006) Relation between vascular risk factors and cognition at age 75. Acta Neurol Scand 114:84–90PubMedCrossRefGoogle Scholar
  22. Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–98PubMedCrossRefGoogle Scholar
  23. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92–105PubMedCrossRefGoogle Scholar
  24. Gimeno D, Marmot MG, Singh MA (2008) Inflammatory markers and cognitive function in middle-aged adults: the Whitehall II study. Psychoneuroendocrinology 33:1322–1334PubMedCrossRefGoogle Scholar
  25. Giunta B, Fernandez F, Nikolic WV, Obregon D, Rrapo E, Town T, Tan J (2008) Inflammaging as a prodrome to Alzheimer's disease. J Neuroinflammation 5:51–66PubMedCrossRefGoogle Scholar
  26. Gunning-Dixon FM, Brickman AM, Cheng JC, Alexopoulos GS (2009) Ageing of cerebral white matter: a review of MRI findings. Int J Geriatric Psychiatry 24:109–117CrossRefGoogle Scholar
  27. Henderson AS, Easteal S, Jorm AF, Mackinnon AJ, Korten AE et al (1995) Apolipoprotein E allele ε4, dementia, and cognitive decline in a population sample. Lancet 346(8987):1387–90PubMedCrossRefGoogle Scholar
  28. Hixson JE, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hha1. J Lipid Res 31(3):545–8PubMedGoogle Scholar
  29. Ishii T, Haga S, Shimizu F (1975) Identification of components of immunoglobins in senile plaques by means of fluorescent antibody technique. Acta Neuropath 32:157–162PubMedCrossRefGoogle Scholar
  30. Jordanova V, Stewart R, Davies E, Sherwood R, Prince M (2008) Markers of inflammation and cognitive decline in an African-Caribbean population. Int J Geriatr Psychiatry 22:966–973CrossRefGoogle Scholar
  31. Kaplan E, Goodglass H, Weintraub S (2001) The Boston naming test. Lippincott Williams and Wilkins, PhiladelphiaGoogle Scholar
  32. Klove H (1963) Clinical neuropsychology. In: Forster FM (ed) The Medical Clinics of North America. Saunders, New YorkGoogle Scholar
  33. Komulainen P, Lakka TA, Kivipelto M, Hassinen M, Penttila IM, Helkala E et al (2007) Serum high sensitivity C-reactive protein and cognitive function in elderly women. Age Aging 36:443–448CrossRefGoogle Scholar
  34. Kuo HK, Yen CJ, Chang CH, Kuo CK, Chen JH, Sorond F (2005) Relation of C-reactive protein to stroke, cognitive disorders, and depression in the general population: systemic review and meta-analysis. Lancet Neurol 4:371–380PubMedCrossRefGoogle Scholar
  35. Lezak MD, Howieson DB, Loring DW (2004) Neuropsychological assessment, 4th edn. Oxford University Press, New YorkGoogle Scholar
  36. Licastro F, Pedrini S, Caputo L, Annoni G, Davis LJ, Ferri C et al (2000) Increased plasma levels of interleukin-1, interleukin-6 and α-antichymotrypsin in patients with Alzheimer's disease: peripheral inflammation or signals from the brain? J Neuroimmunology 103:97–102CrossRefGoogle Scholar
  37. Luciano M, Marioni RE, Gow AJ, Starr JM, Deary IJ (2009) Reverse causation in the association between C-reactive protein and fibrinogen levels and cognitive abilities in an aging sample. Psychosom Med 71:404–9PubMedCrossRefGoogle Scholar
  38. Marsland AL, Petersen KL, Sathanoori R, Muldoon MF, Neumann SA, Ryan C, Flory JD, Manuck SB (2006) Interleukin-6 covaries inversely with cognitive performance among middle-aged community volunteers. Psychosom Med 68:895–903PubMedCrossRefGoogle Scholar
  39. Motta M, Imbesi R, Di Rosa M, Stivala F, Malaguarnera L (2007) Altered plasma cytokine levels in Alzheimer's disease: correlation with the disease progression. Immunol Lett 114:46–51PubMedCrossRefGoogle Scholar
  40. Paganelli R, Di Iorio A, Patricelli L, Ripani F, Sparvieri E, Faricelli R, Iarlori C, Porreca E, Di Gioacchino M, Abate G (2002) Proinflamatory cytokines in sera of elderly patients with dementia: levels in vascular injury are higher than those of mild-moderate Alzheimer's disease patients. Exp Gerontol 37:257–263PubMedCrossRefGoogle Scholar
  41. Phillips AC, Batty GD, van Zanten JJ, Mortensen LH, Deary IJ, Calvin CM, Carroll D (2011) Cognitive ability in early adulthood is associated with systemic inflammation in middle age: the Vietnam experience study. Brain Behav Immun 25:298–301PubMedCrossRefGoogle Scholar
  42. Ravaglia G, Forti P, Mailoi F, Brunetti N, Martelli M, Servadei L et al (2005) Serum C-reactive protein and cognitive function in healthy elderly Italian community dwellers. J Gerontol: Med Sci 60A(8):1017–1021CrossRefGoogle Scholar
  43. Reitan RM, Wolfson D (1993) The Halstead–Reitan neuropsycholgical test battery: theory and clinical interpretation. Neuropsychological Press, TucsonGoogle Scholar
  44. Rey A (1964) L'examen clinique en psychologie. Presses Universitaires de France, ParisGoogle Scholar
  45. Rogers J, Luber-Narod J, Styren SD, Civin WH (1988) Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's Disease. Neurobiol Aging 9:339–349PubMedCrossRefGoogle Scholar
  46. Sachdev P, Brodaty H, Reppermund S, Kochan NA, Trollor JN, Draper B, Slavin M, Crawford J, Kang K, Broe A, Mather K, Lux O, Memory and Ageing Study Team (2010) The Sydney Memory and Ageing Study (MAS): methodology and baseline medical and neuropsychiatric characteristics of an elderly epidemiological non-demented cohort of Australians aged 70–90 years. Int Psychogeriatr 19:1–17Google Scholar
  47. Schram MT, Euser SM, de Craen AJM, Witteman JC, Frolich M, Hofman A, Jolles J, Breteler MMB, Westendorp RGJ (2007) Systemic markers of inflammation and cognitive decline in old age. J Am Geriatr Soc 55:708–716PubMedCrossRefGoogle Scholar
  48. Sheikh JI, Yesavage JA (1986) Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. In: Brink TL (ed) Clinical gerontology: a guide to assessment and intervention. The Hawthorn Press, NY, pp 165–173Google Scholar
  49. Soeda S, Koyanagi S, Kuramoto Y, Kimura M, Oda M, Kozako T, Hayashida S, Shimeno H (2008) Anti-apoptotic roles of the plasminogen activator inhibitor-1 as a neurotropic factor in the central nervous system. Thromb Hemost 100:1014–1020Google Scholar
  50. Spreen O, Benton AL (1969) Neurosensory center comprehensive examination for Aphasia: manual of instructions (NCCEA). University of Victoria, VictoriaGoogle Scholar
  51. SPSS Statistics (2008) Rel. 17.0.0. SPSS Inc, ChicagoGoogle Scholar
  52. Strachan MWJ, Reynolds RM, Frier BM, Mitchell RJ, Price JF (2008) The relationship between type 2 diabetes and dementia. Br Med Bull 88:131–146PubMedCrossRefGoogle Scholar
  53. Stroop JR (1935) Studies of interference in serial verbal reactions. J Exp Psychol 18:643–662CrossRefGoogle Scholar
  54. Sheikh JI, Yesavage JA, Brooks JO 3rd, Friedman L, Gratzinger P, Hill RD, Zadeik A, Crook T (1991) Proposed factor structure of the Geriatric Depression Scale. Int Psychogeriatr 3(1):23–8PubMedCrossRefGoogle Scholar
  55. Salthouse TA (1996) The processing-speed theory of adult age differences in cognition. Psychol Rev 103:403–428PubMedCrossRefGoogle Scholar
  56. Trollor JN, Smith E, Baune BT, Kochan NA, Campbell L, Samaras K, Crawford J, Brodaty H, Sachdev P (2010) Systemic inflammation is associated with MCI and its subtypes - the Sydney Memory and Aging Study. Dement Geriatr Cogn Disord 30(6):569–578PubMedCrossRefGoogle Scholar
  57. Uhlar CM, Whitehead AS (1999) Serum amyloid A, the major vertabrate acute-phase reactant. Eur J Biochem 265:501–523PubMedCrossRefGoogle Scholar
  58. van den Biggelaar AHJ, Gussekloo J, de Craen AJM, Frolich M, Stek ML, van der Mast RC, Westendorp RGJ (2007) Inflammation and interleukin-1 signalling network contribute to depressive symptoms but not cognitive decline in old age. Exp Gerontol 42:693–701PubMedCrossRefGoogle Scholar
  59. Wright CB, Sacco RL, Rundek TR, Delman JB, Rabbani LE, Elkind MSV (2006) Interleukin-6 is associated with cognitive function: the Northern Manhattan Study. J Stroke Cerebrovasc Dis 15:34–38PubMedCrossRefGoogle Scholar
  60. van Dijk EJ, Prins ND, Vermeer SE, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MMB (2005) C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation 112:900–905PubMedCrossRefGoogle Scholar
  61. Warnberg J, Gomez-Martinez S, Romeo J, Diaz LE, Marcos A (2009) Nutrition, inflammation and cognitive function. Neuroimmunomodulation: annuals New York Academy Sci 1153:164–175CrossRefGoogle Scholar
  62. Weaver JD, Huang MH, Albert M, Harris T, Rowe JW, Seeman TE (2002) Interleukin-6 and risk of cognitive decline: MacArthur Studies of Successful Aging. Neurology 59:371–378PubMedCrossRefGoogle Scholar
  63. Wechsler D (1997) Wechsler adult intelligence scale-III. The Psychological Corporation, San AntonioGoogle Scholar
  64. Wechsler D (1981) Wechsler adult intelligence scale — Revised: Manual. Psychological Corporation: New YorkGoogle Scholar
  65. Wilson CJ, Finch CE, Cohen HJ (2002) Cytokines and cognition: the case for a head-to-toe paradigm. J Am Geriatr Soc 50:2041–2056PubMedCrossRefGoogle Scholar
  66. Zuliani G, Cavalieri M, Galvani M, Passaro A, Munani MR, Bosi C et al (2008) Markers of endothelial dysfunction in older subjects with late onset Alzheimer's disease or vascular dementia. J Neurological Sci 272:164–170CrossRefGoogle Scholar
  67. Zuliani G, Ranzini M, Guerra G, Rossi L, Munari MR, Zurlo A, Volpato S, Atti AR, Ble A, Fellin R (2007) Plasma cytokines profile in older subjects with late onset Alzheimer's disease or vascular dementia. J Psychiatr Res 41:686–693PubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association 2011

Authors and Affiliations

  • Julian N. Trollor
    • 1
    • 4
    Email author
  • Evelyn Smith
    • 1
    • 4
  • Emmeline Agars
    • 1
  • Stacey A. Kuan
    • 8
  • Bernhard T. Baune
    • 9
  • Lesley Campbell
    • 6
    • 7
  • Katherine Samaras
    • 6
    • 7
  • John Crawford
    • 4
  • Ora Lux
    • 2
    • 3
    • 4
  • Nicole A. Kochan
    • 2
    • 4
  • Henry Brodaty
    • 4
    • 5
  • Perminder Sachdev
    • 2
    • 4
  1. 1.Department of Developmental Disability Neuropsychiatry, School of PsychiatryUniversity of New South WalesSydneyAustralia
  2. 2.Neuropsychiatric InstitutePrince of Wales HospitalRandwickAustralia
  3. 3.South-Eastern Area Laboratory ServicesPrince of Wales HospitalRandwickAustralia
  4. 4.Brain and Aging Research Program, School of PsychiatryUniversity of New South WalesSydneyAustralia
  5. 5.Dementia Collaborative Research Centre, School of PsychiatryUniversity of New South WalesSydneyAustralia
  6. 6.Garvan Institute of Medical ResearchDarlinghurstAustralia
  7. 7.Department of EndocrinologySt Vincent’s HospitalDarlinghurstAustralia
  8. 8.The Benevolent SocietyPaddingtonAustralia
  9. 9.Discipline of Psychiatry, School of MedicineUniversity of AdelaideAdelaideAustralia

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