The Tumor Necrosis Factor Alpha  308G4A Polymorphism Is Associated with Dementia in the Oldest Old

Bruunsgaard, MD, PhD, Thomas L. Benfield, MD, DrSci, Andersen-Ranberg, MD, PhD,z Jacob v. B. Hjelmborg, MD, PhD,z N. Pedersen, MD, PhD,k Marianne Schroll, MD, DrSci,§z Bente K. Pedersen, MD, Bernard Jeune, MDz

OBJECTIVES: To test the hypothesis that the tumor ne- crosis factor (TNF)

G

A promoter gene poly- morphism is a risk factor in age-related dementia and longevity. DESIGN: A cross-sectional and a longitudinal study. SETTING: A population-based sample of Danish cente- narians. PARTICIPANTS: One hundred-year-old Danes (n

) from ‘‘The Longitudinal Study of Danish Centenarians.’’ Octogenarians (n

) and healthy volunteers aged

to

(n

) served as reference groups. METHODS: Whether the distribution of TNF

GG/ GA/AA genotypes were different in centenarians than in younger age groups was investigated (Fischer exact test). Fur- thermore, whether the TNF

G

A polymorphism was associated with the prevalence of dementia (logistic regression analysis), the plasma level of TNF-a (analysis of variance), and mortality in the following

years (Cox regression anal- ysis) within the cohort of centenarians was tested. RESULTS: The distribution of TNF

genotypes was not different across the three different age groups, but the GA genotype was associated with decreased prevalence of dementia in centenarians. The few centenarians with AA carrier status had higher mortality risk and tended to show higher plasma levels of TNF-a, but the significance was questionable due to a low number of subjects with this

CONCLUSION: It is possible that the TNF   308 A allele is maintained during aging because subjects who are het- erozygous for this polymorphism possess the optimal inflam- matory response with regard to protection against age-related neurodegeneration. J Am Geriatr Soc 52:1361–1366, 2004. Key words: TNF-a; centenarians; dementia; polymorph- ism

METHODS: Whether the distribution of TNF  308 GG/ GA/AA genotypes were different in centenarians than in younger age groups was investigated (Fischer exact test). Fur- thermore, whether the TNF   308 G4A polymorphism was associated with the prevalence of dementia (logistic regression analysis), the plasma level of TNF-a (analysis of variance), and mortality in the following 5 years (Cox regression anal- ysis) within the cohort of centenarians was tested.

the age of 95.1 Although dementia is common, it is not inevitable in the oldest old (e.g., 51% of a population-based cohort of Danish centenarians suffered from mild to severe dementia).2 In this cohort, plasma levels of tumor necrosis factor (TNF)-a were higher than in younger age groups (80- year-olds, a middle-aged group, and young controls), and a high concentration was associated with dementia and pe- ripheral atherosclerosis in centenarians.3 Moreover, TNF-a was a strong predictor of the mortality risk in the following 6 years, independent of dementia and cardiovascular dis- ease, suggesting that TNF-a had specific biological effects and was a marker of frailty in centenarians.4 However, it is still unclear whether high plasma levels of TNF-a was a causative factor or acted as a marker of underlying path- ological processes in dementia and cardiovascular diseases.

RESULTS: The distribution of TNF  308 genotypes was not different across the three different age groups, but the GA genotype was associated with decreased prevalence of dementia in centenarians. The few centenarians with AA carrier status had higher mortality risk and tended to show higher plasma levels of TNF-a, but the significance was questionable due to a low number of subjects with this genotype.

constitute the major categories of age-related dementia, but in centenarians it is difficult to distinguish between the two.2 It has been suggested that neuropathological lesions of AD and cerebrovascular lesions are necessary for the development of reduced cognitive function and dementia in very old people.5 Inflammation is an integral part of the pathology of AD and VaD, and several studies have de- scribed that increased TNF-a levels in the cerebrospinal fluid6,7 and in the circulation accompany both.8,9 It is un- clear whether local inflammatory mechanisms cause dam- age in the central nervous system (CNS) or if they are present to remove the detritus from other, more primary pathological processes. It is also unclear whether endo-

From the Department of Infectious Diseases, Rigshospitalet, University of w Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Hvidovre Hospital, Hvidovre, Denmark; zEpidemiology, Institute of Public Health, and Aging Research Center, University of Southern Denmark, Odense, Denmark; §Research Center for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark; kDanish Veterinary and Food Administration, Division of Nutrition, Copenhagen, Denmark; and z Department of Geriatric Medicine, Bispebjerg Hospital, Copenhagen, Denmark.

From the Department of Infectious Diseases, Rigshospitalet, University of w Copenhagen, Copenhagen, Denmark; Department of Infectious Diseases, Hvidovre Hospital, Hvidovre, Denmark;

pidemiology, Institute of Public Health, and Aging Research Center, University of Southern Denmark, Odense, Denmark; §Research Center for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark;

anish Veterinary and Food Administration, Division of Nutrition, Copenhagen, Denmark; and z Department of Geriatric Medicine, Bispebjerg Hospital, Copenhagen, Denmark. The Danish Medical Research Council supported this study (

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and

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). Address correspondence to Helle Bruunsgaard, Department of Infectious

Address correspondence to Helle Bruunsgaard, Department of Infectious Diseases M7641, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Denmark. E-mail: hellebkemp@os.dk

zed in only 122 centenarians, who formed the basis for the present study.