Epistasis between tau phosphorylation regulating genes (CDK5R1 and GSK-3beta) and Alzheimer's disease risk.
OBJECTIVE
Glycogen synthase kinase-3beta (GSK-3beta) 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-3beta 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-3beta (-50, rs334558) polymorphisms on susceptibility to AD.


RESULTS
Subjects carrying both the CDK5R1 (3'-UTR, rs735555) AA genotype and the GSK-3beta (-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.


CONCLUSIONS
These data support a role for tau phosphorylation regulating genes in risk for AD.
Mateo
I
I
Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Marqués de Valdecilla University Hospital, University of Cantabria, Santander, Spain.
Vázquez-Higuera
J L
JL
Sánchez-Juan
P
P
Rodríguez-Rodríguez
E
E
Infante
J
J
García-Gorostiaga
I
I
Berciano
J
J
Combarros
O
O
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics*; D012307:Risk Factors; D016875:tau Proteins / Q000235:genetics
D021122:Protein Subunits; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3