The Tumor Necrosis Factor Alpha 308G/A 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 necrosis factor (TNF) GA promoter gene polymorphism 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 centenarians.

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 (Fisher exact test). Furthermore, whether the TNF GA 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 analysis) 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 genotype.

CONCLUSION: It is possible that the TNF 308 A allele is maintained during aging because subjects who are heterozygous for this polymorphism possess the optimal inflammatory response with regard to protection against age-related neurodegeneration. J Am Geriatr Soc 52:1361-1366, 2004.

Key words: TNF-a; centenarians; dementia; polymorphism

METHODS: Whether the distribution of TNF 308 GG/GA/AA genotypes were different in centenarians than in younger age groups was investigated (Fisher exact test). Furthermore, whether the TNF 308 GA 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 analysis) within the cohort of centenarians was tested.

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). 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 peripheral atherosclerosis in centenarians. Moreover, TNF-a was a strong predictor of the mortality risk in the following 6 years, independent of dementia and cardiovascular disease, suggesting that TNF-a had specific biological effects and was a marker of frailty in centenarians. However, it is still unclear whether high plasma levels of TNF-a were causative factors or acted as markers of underlying pathological processes in dementia and cardiovascular diseases.

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. 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. Inflammation is an integral part of the pathology of AD and VaD, and several studies have described that increased TNF-a levels in the cerebrospinal fluid and in the circulation accompany both. It is unclear whether local inflammatory mechanisms cause damage 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 endogenous TNF-a is neurotoxic (based largely on acute interventions) or neuroprotective (based largely on studies on genetically modified animals) during inflammatory processes in the CNS (e.g., functional outcomes in TNF-a knockout mice were improved earlier after brain injury than in wild-type mice, butedited:

The study subjected DNA to three cycles at 951°C for 5 seconds, 661°C for 10 seconds, and 721°C for 20 seconds, followed by a melting curve analysis. The melting temperatures were 851°C for the G allele and 651°C for the A allele.

MATERIALS AND METHODS

Centenarians
One hundred and twenty-two centenarians from the Danish Centenarian Study participated in the study, including 28 men. This cohort has been previously described. Briefly, The Danish Centenarian Study is a nationwide epidemiological survey of all individuals living in Denmark who celebrated their 100th birthday from April 1, 1995, to May 31, 1996 (N = 276). All participants were identified in the Civil Registration System in Denmark and admitted to the study as they turned 100. The participation rate was 75% (n = 207). There was no difference between participants and nonparticipants regarding sex and the proportion living at home or in a nursing home. The same geriatrician (KA-R) and a geriatric nurse performed an interview and a physical examination at the place of the subject's residence within five months of the anniversary, and a review of medical records was conducted. Not all subjects agreed to a blood test and a full physical examination; accordingly, the TNF-308 G4A polymorphism was analyzed.