There was no difference in plasma levels of TNF-a be- tween centenarians with the GG and GA genotypes, in ac- cord with other studies.30 TNF-a tended to be higher in subjects with the AA genotypes in the present study, but the difference was not significant. The power of the ANOVA is poor because of the low number of subjects who had the AA genotype, and the large interpersonal variance in plasma levels of TNF-a makes it impossible to assess whether there is a difference. It has been suggested that a multifactorial process regulates the circulating TNF-a, level whereas local TNF-a production might be of greater importance and un- der more control by specific polymorphisms.16

The sample size is small. It was decided not to pool cen- tenarians with GA and AA genotypes because their asso- ciations with dementia and mortality seemed to differ, but the low number of subjects with AA makes it difficult to evaluate the effect of this genotype, as already discussed. However, differences between GG and GA were unaffected when the AA genotype was excluded from the statistical

Few studies have investigated the relationship between the TNF  308 G4A polymorphism and dementia. In pa-

analyses. The  308 A allele is strongly associated with the HLA-DR3 allele,12 and it cannot be excluded that the as- sociations between the polymorphism, dementia, and mor- tality risk in the present study reflect linkage with genes of the major histocompatibility complex. Furthermore, the balance in the cytokine network and combinations of dif- ferent cytokine polymorphisms are probably also important for the clinical outcome. Age-related dementia was not subclassified in the present study because it was difficult to make a differentiation; the onset of dementia was often unknown, most centenarians or their relatives did not agree to a brain autopsy, and it was not possible to perform brain imaging to make a proper evaluation of VaD in this frail cohort. However, half of the demented population had atrial fibrillation or hypertension or experienced a stroke/ transient cerebral ischemia, indicating at least a coexisting vascular component.2 In 12% of the demented centenarians a history of a systemic disease with a potential influence on cognitive function was found (e.g., hypothyroidism, vita- min B or folic acid deficiency, and Parkinson’s disease), 12 but these subjects could also have had AD or VaD.2

Kroeger KM, Steer JH, Joyce DA et al. Effects of stimulus and cell type on the expression of the -

tumour necrosis factor promoter polymorphism. Cytokine

;

:

–

Louis E, Franchimont D, Piron A et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)- stimulated whole blood cell culture in healthy humans. Clin Exp Immunol

;

:

–

Santos AR, Suffys PN, Vanderborght PR et al. Role of tumor necrosis factor- alphaandinterleukin-

promotergenepolymorphismsinleprosy.JInfec

is

;

:

–

Hajeer AH, Hutchinson IV. Influence of TNFalpha gene polymorphisms on TNFalpha production and disease. Hum Immunol

;

:

–

Alvarez V, Mata IF, Gonzalez P et al. Association between the TNFalpha -

A/G polymorphism and the onset-age of Alzheimer disease. Am J Med Genet

;

:

–

Andersen-Ranberg K, Schroll M, Jeune B. Healthy centenarians do not exist, but autonomous centenarians do: A population-based study of morbidity among Danish centenarians. J Am Geriatr Soc

;

:

–

Bruunsgaard H, Ladelund S, Pedersen AN et al. Predicting death from TNF- alpha and IL-

in

-year-old people. Clin Exp Immunol

;

:

–

Barger SW, Horster D, Furukawa K et al. Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: Evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca

accumulation. Proc Natl Acad Sci U S A

;

:

–

Bruc

J,Bolin

,Kind

Setal.Alteredneuronalandmicroglialresponses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med

;

:

–

Tarkowski E, Blennow K, Wallin A et al. Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol

;

:

–

Liu J, Marino MW, Wong G et al. TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nature Med

;

:

–

Hallenbeck JM. The many faces of tumor necrosis factor in stroke. Nature Med

;

:

–

Collins JS, Perry RT, Watson B et al. Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease. The NIMH Alz- heimer’s Disease Genetic Initiative. Am J Med Genet

;

:

–

M

usker SM, Curran MD, Dynan KB et al. Association between poly- morphism in regulatory region of gene encoding tumour necrosis factor alpha and risk of Alzheimer’s disease and vascular dementia: A case-control study. Lancet

;

:

–

Infante J, Llorca J, Berciano J et al. No synergistic effect between -

tumor necrosis factor-alpha promoter polymorphism and apolipoprotein E epsilon

allele in Alzheimer’s disease. Neurosci Lett

;

:

–

Wang XY, Hurme M, Jylha M et al. Lack of association between human longevity andpolymorphismso

L-

cluster,IL-

,IL-

an

NF-alphagenes in Finnish nonagenarians. Mech Ageing Dev

;

:

–

Bonafe M, Olivieri F, Cavallone L et al. A gender-dependent genetic predis- position to produce high levels of IL-

is detrimental for longevity. Eur J Immunol

;

:

–

Kubot

,M

amar

M,Wan

Jetal.Effectsoftumornecrosisfactorgene polymorphisms on patients with congestive heart failure. VEST Investigators for TNF Genotype Analysis. Vesnarinone Survival Trial. Circulation

;

:

–