Odds ratio in a logistic regression analysis with GG as reference.

genotype was independent of sex in the logistic regression analysis (data not shown).

tients with AD, the  308 A allele was associated with a mean age of onset 3 years younger than noncarriers of this allele, but there was no difference in the prevalence of gen- otypes in patients and in healthy controls.17 The latter study17 was a case-control study that was designed to detect differences between patients and controls rather than to evaluate the onset age of symptoms in patients. The onset age of dementia is unknown in the present study. Patients with AD displayed higher intrathecal levels of TNF-a than healthy controls, but levels were not related to the TNF  308 G4A polymorphism, suggesting that inflammation in CNS was due to environmental factors rather than ge- netic makeup.6 Unfortunately, intrathecal cytokine levels were not available in the present study. The combination of the  308 A and the  238 wild-type TNF promoter polymorphisms together with microsatellite TNF-a was associated with AD in a family study.25 Combinations of polymorphisms were not evaluated, and the difference in the study populations (family study vs population-based study) makes it difficult to compare data. Finally, in one study, the TNF  850 C4T polymorphism was associated with sporadic AD and VaD,26 but a later study did not confirm these results.27

The TNF  308 G4A Polymorphism and Mortality Risk in Centenarians

Only eight centenarians were still alive in June 2001, 60 to 74 months after the initial survey. A Cox regression analysis was performed with GG as reference. There was no differ- ence in mortality between centenarians with the GG and GA genotypes, whereas those with the AA genotype had greater mortality risk (GA: hazard ratio (HR) 5 0.71, 95% confidence interval (CI) 5 0.47–1.08, P 5.1; AA: HR 5 3.13, 95% CI 5 1.23–7.97, P 5.02). Hazards were only slightly affected if the analysis was adjusted for the effect of TNF-a levels in plasma and statistically stratified by dementia or sex (data not shown).

The TNF  308 G4A Polymorphism and Circulating Levels of Inflammatory Markers in Centenarians

Levels of Inflammatory Markers in Centenarians There was no difference in plasma levels of TNF-a between the three genotypes within centenarians in a one-way ANOVA (P 5.2), but subjects with the AA genotype tended to have higher plasma levels of TNF-a than the other two genotypes (medians (25th–75th percentiles) GG: 4.3 pg/mL (2.4–6.1), n 5 70; GA: 3.9 pg/mL (2.0–5.5), n 5 35; AA: 7.0 pg/mL (3.9–9.2), n 5 5). There was no difference in circu- lating levels of IL-6, IL-8, or CRP between the three dif- ferent genotypes (data not shown).

The prevalence of the TNF  308 genotypes was un- altered across age groups in the present study. Likewise, there was no difference in the genotype distribution between Finnish nonagenarians and younger controls.28 Nevertheless, in centenarians in the present study, those with the AA genotype tended to have high plasma levels of TNF-a, which was associated with increased mortality risk in the following years, but the low number of centenarians with this genotype calls into question the reliability of this result. However, one may speculate that the TNF   308 A allele is maintained during aging because subjects who are het- erozygous for this polymorphism possess the optimal in- flammatory response against age-degenerative processes in the CNS. It is possible that genetic factors are important for long-term survival in subjects who have already survived to advanced age despite considerable comorbidity. Consistent with this, the IL-6  174 G4C promoter polymorphism was also a risk factor beyond the age of 100 years in a cross- sectional study of different Italian age groups.29

DISCUSSION

The novel finding in the present study was that, contrary to the hypothesis, the TNF  308 GA genotype was associ- ated with a lower prevalence of dementia than the GG genotype in centenarians. This result suggests that a bal- anced TNF-a response possesses the optimal inflammatory response against age-related degenerative processes in the CNS. Consistent with this, it has been demonstrated that TNF-a protects against toxicity mediated by amyloid b- peptide,20 and mice lacking p55 and p75 TNF receptors showed exacerbated neuronal injury in response to focal cerebral ischemia or epileptic seizures than wild-type mice.21 Furthermore, cerebrospinal fluid levels of TNF-a and CD95 were negatively correlated in patients with AD, and the incidence of B-cell lymphoma-2 was greater in supernatants of TNF-exposed neuronal cell cultures than in control cultures, suggesting that TNF-a has a neuroprotec- tive effect by inhibiting apoptosis.22 In an animal model of multiple sclerosis, inactivation of the TNF gene converted disease-resistant mice to a state of high susceptibility, and treatment with TNF dramatically reduced disease severity in TNF   /  and TNF1/1 mice, demonstrating that TNF-a limited the extent and duration of severe CNS pathology.23 However, exogenous TNF-a has also been associated with neurotoxicity, and it has been suggested that TNF-a contributes to early neuronal injury but could improve recovery.10 The role of TNF-a in CNS repair is not yet well- described,24 but the present data indicate that this aspect is important in centenarians who have survived to advanced