Arg972 insulin receptor substrate-1 polymorphism and risk and severity of Alzheimer's disease.

We explored the association between the Arg972 insulin receptor substrate-1 (IRS1) polymorphism and the risk and severity of Alzheimer's disease (AD). We genotyped the Arg972 IRS1 (rs1801278) polymorphism in 1123 pairs of age, sex, body mass index, residence area and education level-matched Han Chinese AD patients and controls. AD severity was assessed with Mini-Mental State Examination (MMSE) scores. The AA (homozygous Arg972 IRS1) and GA (heterozygous Arg972 IRS1) genotypes were associated with an increased risk of AD after adjustment for comorbidities including type 2 diabetes mellitus, coronary heart disease, and hypertension (p<0.001; adjusted odds ratio [OR] 3.93 and 2.90, respectively). The A allele was associated with an increased risk of AD after adjustment for comorbidities (p<0.001; adjusted OR 2.26; 95% confidence interval 1.92-2.80). The percentage of Arg972 IRS1 AA homozygotes was higher in the MMSE score ⩽14 category than in the MMSE score 15-26 category overall and in each age group (p<0.001), while the wild type IRS1 GG homozygotes were predominantly found in the MMSE score 15-26 category overall and in each age group. The GG homozygote group had higher MMSE score than the GA heterozygote group, which in turn had higher MMSE score than the AA homozygote group overall and in each age group (p<0.05). In conclusion, the Arg972 IRS1 polymorphism is an independent risk factor for AD and the A allele has a gene dosage effect on AD severity in Han Chinese. This study adds fresh insights into the pathogenesis of AD.