BACKGROUND: Genetic polymorphisms of APO-E, homocysteine, and the IL-1 gene cluster (IL-1A, IL-1B, receptor antagonist IL-1RN) are associated with sporadic Alzheimer's disease and may involve interdependent pathways of neuronal toxicity. OBJECTIVE: To determine whether these polymorphisms and the genetic determinants of homocysteine (methylenetetrahydrofolate reductase, MTHFR; methionine synthase, MTR; transcobalamin, TC) are associated with an increased risk of severe dementia in Alzheimer's disease. METHODS: 152 patients with Alzheimer's disease and 136 controls were studied. The association of occurrence and dementia severity (Reisberg score <6 and >or=6) of Alzheimer's disease with APO-E, IL-1A, IL-1B, IL-1RN, MTHFR677 C-->T and 1298A-->C, MTR 2756 A-->G, and TC 776 C-->G polymorphisms was evaluated by multivariate logistic regression analysis after adjustment for age, sex, and age of onset of Alzheimer's disease. RESULTS: IL-1A TT and IL-1B CT/TT associated genotypes were at risk of Alzheimer's disease (odds ratio 4.80 (95% confidence interval, 1.32 to 17.40), p = 0.017); the MTR 2756 AA genotype was at risk of severe dementia (OR 2.97 (1.23 to 7.21), p = 0.016); IL-1 RN*2 was protective (OR 0.28, (0.11 to 0.69), p = 0.006). Allele epsilon4 of the APO-E and IL-1B CC genotypes increased the risk of severe Alzheimer's disease associated with the MTR 2756 AA genotype by 3.3-fold and 1.5-fold, respectively. CONCLUSIONS: Distinct determinants of the IL-1 gene cluster are related to the generation and progression of Alzheimer's disease. MTR only influences progression of the disease, which may be enhanced by carriage of allele epsilon4 of APO-E.
BACKGROUND: Genetic polymorphisms of APO-E, homocysteine, and the IL-1 gene cluster (IL-1A, IL-1B, receptor antagonist IL-1RN) are associated with sporadic Alzheimer's disease and may involve interdependent pathways of neuronal toxicity. OBJECTIVE: To determine whether these polymorphisms and the genetic determinants of homocysteine (methylenetetrahydrofolate reductase, MTHFR; methionine synthase, MTR; transcobalamin, TC) are associated with an increased risk of severe dementia in Alzheimer's disease. METHODS: 152 patients with Alzheimer's disease and 136 controls were studied. The association of occurrence and dementia severity (Reisberg score <6 and >or=6) of Alzheimer's disease with APO-E, IL-1A, IL-1B, IL-1RN, MTHFR677 C-->T and 1298A-->C, MTR 2756 A-->G, and TC 776 C-->G polymorphisms was evaluated by multivariate logistic regression analysis after adjustment for age, sex, and age of onset of Alzheimer's disease. RESULTS:IL-1A TT and IL-1B CT/TT associated genotypes were at risk of Alzheimer's disease (odds ratio 4.80 (95% confidence interval, 1.32 to 17.40), p = 0.017); the MTR 2756 AA genotype was at risk of severe dementia (OR 2.97 (1.23 to 7.21), p = 0.016); IL-1 RN*2 was protective (OR 0.28, (0.11 to 0.69), p = 0.006). Allele epsilon4 of the APO-E and IL-1B CC genotypes increased the risk of severe Alzheimer's disease associated with the MTR 2756 AA genotype by 3.3-fold and 1.5-fold, respectively. CONCLUSIONS: Distinct determinants of the IL-1 gene cluster are related to the generation and progression of Alzheimer's disease. MTR only influences progression of the disease, which may be enhanced by carriage of allele epsilon4 of APO-E.
Authors: J-L Guéant; G Anello; P Bosco; R-M Guéant-Rodríguez; A Romano; C Barone; P Gérard; C Romano Journal: J Neurol Neurosurg Psychiatry Date: 2005-05 Impact factor: 10.154
Authors: D R Howlett; S T Bate; S Collier; A Lawman; T Chapman; T Ashmeade; I Marshall; P J B Anderson; K L Philpott; J C Richardson; C J Hille Journal: Exp Brain Res Date: 2011-08-18 Impact factor: 1.972