Association between polymorphism in regulatory region of gene encoding tumour necrosis factor α and risk of Alzheimerʹs disease and vascular dementia: a case-control study

Background Deposition of β-amyloid in the brains of patients with Alzheimerʹs disease is thought to precede a chain of events that leads to an inflammatory response by the brain. We postulated that genetic variation in the regulatory region of the gene for the proinflammatory cytokine tumour necrosis factor α (TNF-α) leads to increased risk of Alzheimerʹs disease and vascular dementia. Methods A polymorphism in the regulatory region of the TNF- α gene was analysed in a case-control study. The polymorphism (C-850T) was typed in 242 patients with sporadic Alzheimerʹs disease, 81 patients with vascular dementia, 61 stroke patients without dementia, and 235 normal controls. These groups of individuals were also genotyped for the apolipoprotein E polymorphism, and the vascular dementia and stroke groups were typed at the HLADR locus. Findings The distribution of TNF-α genotypes in the vascular dementia group differed significantly from that in the stroke and normal control groups, giving an odds ratio of 2·51 (95% CI 1·49–4·21) for the development of vascular dementia for individuals with a CT or TT genotype. Logistic regression analysis indicated that the possession of the T allele significantly increased the risk of Alzheimerʹs disease associated with carriage of the apolipoprotein var epsilon4 allele (odds ratio 2·73 [1·68–4·44] for those with apolipoprotein E var epsilon4 but no TNF-α T, vs 4·62 [2·38–8·96] for those with apolipoprotein E var epsilonin;4 and TNF-α T; p=0·03). Interpretation Possession of the TNF-α T allele significantly increases the risk of vascular dementia, and increases the risk of Alzheimerʹs disease associated with apolipoprotein E. Although further research is needed, these findings suggest a potential role for anti-inflammatory therapy in vascular dementia and Alzheimerʹs disease, and perhaps especially in patients who have had a stroke.