Epistasis between tau phosphorylation regulating genes (CDK5R1 and GSK-3β) and Alzheimer's disease risk

• Published in: Acta neurologica Scandinavica Vol. 120; no. 2; pp. 130 - 133
• Main Authors: Mateo, I., Vázquez-Higuera, J. L., Sánchez-Juan, P., Rodríguez-Rodríguez, E., Infante, J., García-Gorostiaga, I., Berciano, J., Combarros, O.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2009; Blackwell
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - etiology; Alzheimer Disease - genetics; Alzheimer's disease; Biological and medical sciences; Case-Control Studies; Cyclin-Dependent Kinase 5 - genetics; cyclin-dependent kinase 5 regulatory subunit 1; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; epistasis; Epistasis, Genetic; Female; gene polymorphism; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 beta; glycogen synthase kinase-3β; Humans; Male; Medical sciences; Middle Aged; Neurology; Phosphorylation - genetics; Protein Subunits - genetics; Risk Factors; tau Proteins - genetics; Nervous system diseases; Phosphorylation; epistasis; Enzyme; Alzheimer disease; cyclin-dependent kinase 5 regulatory subunit 1; Transferases; gene polymorphism; Subunit; Cyclin-dependent kinase 5; Cerebral disorder; Gene; Tau protein; Glycogen synthase kinase-3β; Central nervous system disease; Risk factor; Degenerative disease; Alzheimer's disease; Polymorphism
• ISSN: 0001-6314; 1600-0404
• DOI: 10.1111/j.1600-0404.2008.01128.x

Objective –  Glycogen synthase kinase‐3β (GSK‐3β) and cyclin‐dependent kinase 5 (CDK5) have been implicated as two major protein kinases involved in the abnormal hyperphosphorylation of tau in Alzheimer’s disease (AD) brain, and the development of neurofibrillary tangles. CDK5 regulatory subunit 1 (CDK5R1) encodes for p35, a protein required for activation of CDK5. As both CDK5R1 and GSK‐3β genes are related to phosphorylation of tau, we examined the combined contribution of these genes to the susceptibility for AD. Methods –  In a case–control study in 283 AD patients and 263 healthy controls, we examined the combined effects between CDK5R1 (3′‐UTR, rs735555) and GSK‐3β (−50, rs334558) polymorphisms on susceptibility to AD. Results –  Subjects carrying both the CDK5R1 (3′‐UTR, rs735555) AA genotype and the GSK‐3β (−50, rs334558) CC genotype had a 12.5‐fold decrease in AD risk (adjusted by age, sex and APOE status OR = 0.08, 95% CI = 0.01–0.76, P = 0.03), suggesting synergistic effects (epistasis) between both genes. Conclusion –  These data support a role for tau phosphorylation regulating genes in risk for AD.