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

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 73; no. 3; pp. 261 - 266
• Main Authors: Liolitsa, D, Powell, J, Lovestone, S
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.09.2002; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: ADRDA; Age Factors; Aged; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Alzheimer's Disease and Related Disorders Association; amyloid precursor protein; Apolipoproteins; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; APP; association study; Biological and medical sciences; Brain research; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia; Enzymes; Epidemiology; Female; Gene Frequency; gene polymorphisms; Genotype; Genotype & phenotype; glycogen synthase kinase 3; GSK 3; Health risk assessment; Humans; IGF 1; insulin; Insulin - metabolism; Insulin resistance; Insulin Resistance - genetics; insulin-like growth factor 1; Kinases; Male; Medical sciences; National Institute of Neurological and Communicative Disorders and Stroke; Neurology; NINCDS; odds ratio; Older people; p85α regulatory subunit of phosphatidyl inositol 3 kinase; Pathogenesis; phosphatidyl inositol 3 kinase; Phosphatidylinositol 3-Kinases - genetics; Phosphoprotein Phosphatases - genetics; PI3-K; PIK3R1; PKB; Polymerase chain reaction; Polymorphism; Polymorphism, Genetic - genetics; PP1; PPPIR3; protein kinase B; Protein Phosphatase 1; Regression analysis; regulatory subunit 3 of protein phosphatase 1; Risk Factors; Signal transduction; United Kingdom > UK; Human; Nervous system diseases; Late; Enzyme; Alzheimer disease; Phosphoprotein phosphatase; Transferases; Phosphoric monoester hydrolases; Genotype; Esterases; Subunit; Genetic determinism; Insulin; Cerebral disorder; 1-Phosphatidylinositol 3-kinase; Allele; Age of onset; Gene; Central nervous system disease; Risk factor; Hydrolases; Degenerative disease; Polymorphism
• ISSN: 0022-3050; 1468-330X
• DOI: 10.1136/jnnp.73.3.261

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.