Early ReportAssociation 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
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
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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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2015, Free Radical Biology and MedicineCitation Excerpt :Vascular dementia (VD) is the second most common cause of dementia after Alzheimer's disease (AD) [3], and recently emerged hypothesis considers VD as a risk factor for AD development [4,5]. The majority of the patients are suffered from cognitive deficits partially due to the cerebral hypoperfusion-induced ischemic, oxidative stress and inflammatory responses during the pathological process of VD [6,7]. Although highly needed, there are currently limited specific strategies for the treatment or prevention of VD [8,9].