Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 beta gene and promoter in late onset Alzheimer's disease

Alzheimer's disease (AD) is a disorder characterised by a progressive deterioration in memory and other cognitive functions. Glycogen synthase kinase 3 beta (GSK3 beta) phosphorylates the microtubule associated protein tau at sites that are aberrantly phosphorylated in AD. GSK3 beta binds to presenilin 1 and plays a role in wnt and insulin signalling cascades, both of which have been proposed to be linked to AD. Moreover GSK3 beta activity may be altered in AD brain. These observations suggest a central role for GSK3 beta in AD and led us to investigate GSK3 beta as a candidate gene for AD. We sought to identify sequence variations in the gene and its promoter, as these could have an effect on activity and expression leading to abnormal function. Sequencing over 3000 bp of the GSK3 beta putative promoter revealed there to be five sequence variations, two of which were common (>10%), However on further examination none of these, either alone or in synergy, had any association with late onset AD. Stratification of the data by APOE epsilon4 status also produced no significant association, Sequencing of the GSK3 beta coding region revealed no variations. This would suggest that the aberrant phosphorylation of tau by GSK3 beta in AD is not due to sequence variations in the gene or its promoter.