McCusker S M, Curran M D, Dynan K B, McCullagh C D, Urquhart D D, Middleton D, Patterson C C, McIlroy S P, Passmore A P
Department of Geriatric Medicine, Queen's University of Belfast, UK.
Lancet. 2001 Feb 10;357(9254):436-9. doi: 10.1016/s0140-6736(00)04008-3.
Deposition of beta-amyloid in the brains of patients with Alzheimer's 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 alpha (TNF-alpha) leads to increased risk of Alzheimer's disease and vascular dementia.
A polymorphism in the regulatory region of the TNF-alpha gene was analysed in a case-control study. The polymorphism (C-850T) was typed in 242 patients with sporadic Alzheimer's 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 HLA-DR locus.
The distribution of TNF-alpha 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 Alzheimer's disease associated with carriage of the apolipoprotein E epsilon4 allele (odds ratio 2.73 [1.68-4.44] for those with apolipoprotein E epsilon4 but no TNF-alpha T, vs 4.62 [2.38-8.96] for those with apolipoprotein E epsilon4 and TNF-alpha T; p=0.03).
Possession of the TNF-alpha T allele significantly increases the risk of vascular dementia, and increases the risk of Alzheimer's disease associated with apolipoprotein E. Although further research is needed, these findings suggest a potential role for anti-inflammatory therapy in vascular dementia and Alzheimer's disease, and perhaps especially in patients who have had a stroke.
阿尔茨海默病患者大脑中β-淀粉样蛋白的沉积被认为先于一系列导致大脑炎症反应的事件。我们推测促炎细胞因子肿瘤坏死因子α（TNF-α）基因调控区域的遗传变异会增加患阿尔茨海默病和血管性痴呆的风险。
在一项病例对照研究中分析了TNF-α基因调控区域的多态性。对242例散发性阿尔茨海默病患者、81例血管性痴呆患者、61例无痴呆的中风患者和235名正常对照者进行了该多态性（C-850T）分型。还对这些个体组进行了载脂蛋白E多态性基因分型，对血管性痴呆组和中风组进行了HLA-DR位点分型。
血管性痴呆组中TNF-α基因型的分布与中风组和正常对照组显著不同，CT或TT基因型个体患血管性痴呆的优势比为2.51（95%可信区间1.49-4.21）。逻辑回归分析表明，携带T等位基因显著增加了与载脂蛋白Eε4等位基因携带者相关的阿尔茨海默病风险（载脂蛋白Eε4但无TNF-αT者的优势比为2.73[1.68-4.44]，而载脂蛋白Eε4和TNF-αT者为4.62[2.38-8.96]；p=0.03）。
携带TNF-αT等位基因显著增加血管性痴呆风险，并增加与载脂蛋白E相关的阿尔茨海默病风险。尽管需要进一步研究，但这些发现提示抗炎治疗在血管性痴呆和阿尔茨海默病中可能发挥作用，尤其是在中风患者中。
