Alpha2-Heremans-Schmid glycoprotein (AHSG), also known as fetuin-A, is a highly glycosylated protein which has been recently reported to be decreased in the cerebrospinal fluid of patients with Alzheimer's disease. AHSG is genetically polymorphic and two common alleles, AHSG*1 and AHSG*2, have been described. The purpose of this study was to investigate the distribution of AHSG gene polymorphism in 235 Caucasian Italian patients with late-onset Alzheimer's disease (LOAD) and 235 age- and gender-matched healthy controls. In patients with LOAD, the genotype distribution was 184 AHSG 1*1, 44 AHSG 1*2, 7 AHSG 2*2, and was significantly different from that observed in the 235 control subjects (117 AHSG 1*1, 103 AHSG 1*2, 15 AHSG 2*2) (chi(2)=41.50, P<0.0001). After allowance for age, gender and APOE epsilon4 status, multivariate logistic regression analysis revealed that the adjusted odds ratio for the development of LOAD in AHSG 1*1 homozygotes was 3.90 (95% CI: 2.58-5.90, P<0.0001). These results suggest that the AHSG gene polymorphism may be associated with LOAD in Italians. Additional studies are warranted to examine the biological relevance of AHSG in the pathophysiology of neurodegenerative disorders.