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Genetic variability in the insulin signalling pathway may contribute to the risk of late onset Alzheimer's disease
  1. D Liolitsa,
  2. J Powell,
  3. S Lovestone
  1. Department of Neuroscience and Department of Old Age Psychiatry, Institute of Psychiatry, Denmark Hill, SE5 8AF, London, UK
  1. Correspondence to:
 Dr D Liolitsa;


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 p85α 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 II diabetes.

Methods: Analysis of the Met326Ile 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 (CI) 1.17 to 3.74, p = 0.01; alleles: OR 1.99, 95% CI 1.17 to 3.40, p = 0.01) for the Met326Ile 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% CI 1.03 to 3.30, p = 0.04; alleles: OR 1.68, 95% CI 0.98 to 2.88, p = 0.06). Both polymorphisms were tested for their interactions with sex and the presence of the apolipoprotein E ε4 allele.

Conclusions: The results support the hypothesis for a common genetic aetiology predisposing to insulin resistance and AD.

  • Alzheimer's disease
  • association study
  • insulin
  • gene polymorphisms
  • AD, Alzheimer's disease
  • ADRDA, Alzheimer's Disease and Related Disorders Association
  • APP, amyloid precursor protein
  • GSK 3, glycogen synthase kinase 3
  • IGF 1, insulin-like growth factor 1
  • NINCDS, National Institute of Neurological and Communicative Disorders and Stroke
  • OR, odds ratio
  • PI3-K, phosphatidyl inositol 3 kinase
  • PIK3R1, p85α regulatory subunit of phosphatidyl inositol 3 kinase
  • PKB, protein kinase B
  • PP1, protein phosphatase 1
  • PPPIR3, regulatory subunit 3 of protein phosphatase 1

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  • Competing interests: none declared