Alzheimer's disease (AD) is a complex disease with the possible involvement of several genes. The APOE*4 allele has been documented to be a major risk factor for sporadic late-onset AD, but it is neither necessary nor sufficient to cause the disease. Cathepsin G, a serine protease found commonly in the azurophillic granules of neutrophils, has been reported to possess some beta-secretase like properties, and thus may be involved in the processing of amyloid precursor protein (APP). Recently, an A-->G polymorphism has been reported in exon 4 of the cathepsin G gene, which changes the codon AAC ((125) Asp) to AGC ((125)Ser). In this study, we have investigated the association of this polymorphism with sporadic late-onset AD. We screened DNA samples from 464 late-onset AD cases and 310 age-matched controls. No significant association was seen between this polymorphism and AD. When the data were stratified by the APOE*4 carrier status, no significant difference was seen either. Our data show no effect of this cathepsin G polymorphism in AD. Characterization of additional polymorphisms in this gene may provide more conclusive answers.