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

Objective - Glycogen synthase kinase-3 beta (GSK-3 beta) 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-3 beta 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-3 beta (-50, rs334558) polymorphisms on susceptibility to AD. Results - Subjects carrying both the CDK5R1 (3'-UTR, rs735555) AA genotype and the GSK-3 beta (-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.