Aberrant phosphorylated tau is the major component of the neurofibrillary tangles in Alzheimer’s disease (AD) brains. Glycogen synthase kinase-3β (GSK-3β) phosphorylates tau protein, and increased GSK-3β expression has been associated with neurofibrillary tangles. Saitohin (STH) is a recently identified protein that shares tissue expression pattern with tau, and previous evidence in the Spanish population indicated that a polymorphism at codon 7 (Q7R) of the STH gene was associated with late-onset AD. Since both GSK-3β and STH are related to tau, we examined the association between a polymorphism in the promoter region (–50) of the GSK-3β gene and AD, either through an independent effect or through interaction with the STH (Q7R) polymorphism, in a well-defined group of 333 sporadic AD patients and 307 control subjects from Spain. The current study reveals that GSK-3β (–50) TT genotype is associated with an increased risk (OR 1.99, p = 0.003) for late-onset (after the age of 72 years) AD. Our results indicate that both the GSK-3β (–50) and STH (Q7R) polymorphisms increase the risk of late-onset (subjects >72 years) AD, although they appear to be independent and thus not to interact synergistically.