Alpha 2-Macroglobulin gene (A2M) has been recognized as a candidate gene for late-onset Alzheimer's disease (AD), but the association between several polymorphisms in A2M gene and risk for AD remained controversial. Moreover, little is known regarding the effects of polymorphisms in A2M promoter region on AD susceptibility. Our study aimed to detect polymorphisms in A2M promoter region, and then evaluate their relationship to sporadic AD (SAD). One single nucleotide polymorphism (-88A/G) in proximal promoter region was found by sequencing, and further analyzed with an established 25T/G polymorphism in 179 SAD patients and 179 age-gender-matched controls. Allele A in -88A/G polymorphism was more prevalent in cases, with a 1.7-folded risk for SAD (OR = 1.74, 95%CI 1.05-2.91, P= 0.031), while G allele in 25T/G was less prevalent in cases, with a 43% reduced risk for SAD (OR= 0.57, 95%CI 0.36-0.89, P= 0.013). After adjusted the effects of age, gender and APOE epsilon 4 allele status in logistic regression model, the protective effects of -88G and 25G on SAD still remained. Individuals who carried haplotype -88G/25G had a significant 44% reduced risk for SAD compared to those who did not carry (OR = 0.56, 95%CI 0.34-0.94, P= 0.027), while haplotype -88A/25T carriers had an increased risk for SAD compared to those who did not carry (OR = 1.77, 95%CI 1.06-2.96, P= 0.027). Our study supports that haplotype -88G/25G might play a protective role in the development of SAD, and the protective effects of -88G and 25G were independent of APOE kappa 4 allele. (C) 2010 Elsevier Ireland Ltd. All rights reserved.