Elsevier

The Lancet

Volume 357, Issue 9254, 10 February 2001, Pages 436-439
The Lancet

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

https://doi.org/10.1016/S0140-6736(00)04008-3Get rights and content

Summary

Background

Deposition of β-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 α (TNF-α) leads to increased risk of Alzheimer's 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 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 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 Alzheimer's disease associated with carriage of the apolipoprotein ɛ4 allele (odds ratio 2·73 [1·68–4·44] for those with apolipoprotein E ɛ4 but no TNF-α T, vs 4·62 [2·38–8·96] for those with apolipoprotein E ɛin;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 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.

Introduction

The incidence of dementia has increased with the changing demographics of more developed countries. Alzheimer's disease is the most prevalent form of dementia, but vascular dementia is an increasingly important cause of this debilitating illness. Although much research has been applied to the identification of genetic risk factors for Alzheimer's disease, and possession of the ɛ4 allele of apolipoprotein E is now a widely accepted risk, relatively little has been documented in the case of vascular dementia.

Although infiltration of lymphocytes and macrophages occurs in the central nervous system, notably after stroke or trauma, brains of patients with neurodegenerative disease generally do not show classic signs of inflammation. However, research has suggested that inflammatory mechanisms could cause a substantial amount of the tissue destruction that invariably leads to dementia.1 In Alzheimer's disease, the neuropathological hallmarks are accompanied by reactive microglia that display inflammatory and immune markers.2 Furthermore, cross-sectional and longitudinal studies indicate that non-steroidal anti-inflammatory drugs prevent or delay the onset of dementia.3

Despite the fact that the effects of inflammation in vascular dementia have not been as intensively studied reactive microglia have been documented in cerebral ischaemia, possibly as early mediators of tissue damage.4 Furthermore, some researchers have postulated that neuroinflammatory processes lead to increased formation of reactive oxygen and nitrogen species which are involved in the development of neurodegenerative disease.5 In rats, all forms of ischaemia or inflammation have been associated with amyloid deposition.6 This process could lead to endothelial necrosis and propagation of cytokines causing further amyloid deposition, and resulting in neurodegeneration and cognitive impairment in some strokes.7, 8, 9

We postulated that genetic variation in proinflammatory cytokines could influence the aetiology of Alzheimer's disease, vascular dementia, or both. The cytokine tumour necrosis factor α (TNF-α) is an appropriate candidate because significantly higher intrathecal concentrations of this molecule have been found in patients with Alzheimer's disease and those with vascular dementia10. Furthermore, it has been postulated to induce apoptosis in neuronal cells by increasing production of reactive oxygen species.11 We analysed the prevalence of a polymorphism in the regulatory region of the TNF-α gene in patients with Alzheimer's disease, patients with vascular dementia, stroke patients without dementia, and healthy controls from the relatively genetically homogeneous population of Northern Ireland, UK.12

Section snippets

Participants

Patients and controls were white, and at least their parents and grandparents had been born in Northern Ireland. All participants with a strong family history of dementia, greater than one first degree relative, were excluded. Blood samples from patients with Alzheimer's disease and vascular dementia were obtained through the Memory Clinic, Belfast City Hospital, and by referral from the Alzheimer's Disease Society. The mean age of patients with Alzheimer's disease (n=242) was 75·4 years (SD

Results

Table 1 shows the TNF-α genotypes, which showed no evidence of departure from Hardy-Weinberg equilibrium. The distribution of genotypes in the vascular dementia group differed significantly from that in the stroke and healthy control groups. The odds ratio for TNF-α T carriers (CT or TT genotypes) versus non-carriers (CC genotype) in the vascular dementia and stroke groups was 2·32 (95% CI 1·18–4·58). When the vascular dementia group was compared with the healthy control group, the odds ratio

Discussion

This report presents evidence which indicates that the C-850T polymorphism in the TNF-α gene is a risk factor for vascular dementia in Northern Ireland. In addition, the χ2 test for trend indicated an approximate doubling of the risk for individuals with two TNF-α T alleles (TT genotype) compared with people with one (CT genotype). Lack of an association with the HLA-DR region suggests that the influence on risk of vascular dementia exerted by the polymorphism comes from the TNF-α gene, or a

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