Abstract

Background: The NOTCH4 gene is located at 6p21.3, a site shown in several studies to have significant linkage with Alzheimer’s disease.

Objective: To investigate the potential impact of two polymorphisms within this gene on the risk of developing Alzheimer’s disease.

Methods: Genotyping of promoter and 5′-UTR polymorphisms was done in Scottish, English, and French populations. The potential functionality of the 5′-UTR polymorphism was assessed by testing its impact on Aβ load in Alzheimer brains and also by undertaking electrophoretic mobility shift assays and transfection experiments.

Results: No association of the Notch4 polymorphisms alone with the disease was observed in any of the populations. However, an interaction of the 5′-UTR C/T polymorphism with the ε4 allele of the APOE gene was detected in United Kingdom populations but not in the French. No relation between the 5′-UTR polymorphism and Aβ loads was detected overall or in the presence or absence of the ε4 allele. No DNA protein specific binding was found with proteins from neuroblastoma, glioma, or astrocytoma cells, and no allele dependent transcriptional activity was detected.

Conclusions: No association between two NOTCH4 polymorphisms alone and Alzheimer’s disease was observed in the three populations, but there was evidence of an increased risk associated with the 5′-UTR CC genotype in ε4 bearers in the United Kingdom. As no functionality for this polymorphism could be determined, it is likely that the interaction is spurious or results from a linkage disequilibrium of this 5′-UTR polymorphism with another marker elsewhere in the 6p21.3 locus.