Genetic variability in the insulin signalling pathway may contribute to the risk of late onset Alzheimer's disease

Objective: To test the hypothesis that polymorphic variation in insulin signalling genes may underlie the shared risk of dysfunctional insulin signalling and late onset Alzheimer's disease (AD). The p85alpha subunit of phosphatidyl inositol 3 kinase (PIK3R1) and the regulatory subunit 3 of protein phosphatase 1 (PPP1R3) were selected as candidate genes because both encode key proteins involved in insulin signalling and because polymorphisms in these genes have been previously implicated in insulin resistance or type 11 diabetes. Methods: Analysis of the Met326lle PIK3R1 and the Asp905Tyr PPP1R3 polymorphisms in 202 patients with late onset AD and 160 or 170 age matched normal subjects. Results: Logistic regression analysis using the recessive genetic model showed significant differences in genotype and allelic frequencies between the AD group and normal controls (genotypes: odds ratio (OR) 2.09, 95% confidence interval (Cl) 1.17 to 3.74, p = 0.01; alleles: OR 1.99, 95% Cl 1.17 to 3.40, p = 0.01) for the Met326lle PIK3R1 polymorphism that were female specific. Additionally, in the dominant genetic model a marginally significant association in genotype frequencies between the Asp905Tyr PPP1R3 polymorphism and AD was observed (genotypes: OR 1.85, 95% Cl 1.03 to 3.30, p = 0.04; alleles: OR 1.68, 95% Cl 0.98 to 2.88, p = 0.06). Both polymorphisms were tested for their interactions with sex and the presence of the apolipoprotein E epsilon4 allele. Conclusions: The results support the hypothesis for a common genetic aetiology predisposing to insulin resistance and AD.