Apolipoprotein D (apoD) is a lipoprotein-associated glycoprotein that is increased in the hippocampus and cerebrospinal fluid of patients with Alzheimer's disease (AD), which implies that apoD might be involved in the pathogenesis of AD. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing techniques to screen all exons (1-5) and the flanking exon-intron boundaries of the apoD gene (APOD). Thirty subjects [15 sporadic AD (SAD) patients and 15 controls] were randomly selected and tested for APOD variations by direct sequencing. Two APOD polymorphisms (rs5952T/C and rs1568566C/T) were detected. We further investigated APOD polymorphisms in 256 SAD patients and 294 healthy subjects from a North Chinese population to investigate whether they affect the risk of SAD. Logistic analysis revealed that both rs5952 C and rs1568566 T alleles increase the risk of SAD [rs5952, adjusted odds ratio (OR) 1.817, 95% confidence interval (CI) 1.237-2.669, P = 0.002; rs1568566, adjusted OR 1.563, 95% CI 1.060-2.306, P = 0.024). The rs5952T-rs1568566C haplotype showed lower risk of SAD (OR 0.421, 95% CI 0305-0.583, P = 0.000). Case-control analysis revealed that the rs5952T-rs1568566C haplotype could serve as a novel defendant factor against SAD. APOD polymorphisms might play an important role in modifying SAD risk in some way. (c) 2008 Published by Elsevier B.V.