Low-density lipoprotein receptor-related protein1 (LRP1) and alpha-2-macroglobulin (A2M) are candidate genes for sporadic Alzheimer's disease (SAD). It is not clear whether the LRP1 exon 3 and A2M exon 24 polymorphisms are associated with SAD. In the present study, we used direct sequencing to genotype the LRP1 C766T (rs1799986) polymorphism in exon 3 and the A2M I1000V (rs669) polymorphism in exon 24 in 364 patients with SAD and 291 healthy control subjects from the Northern Chinese Han population. The distributions of LRP1 genotypes (chi-squared [χ(2)]=7.25, degrees of freedom [d.f.]=2, p=0.027) and alleles (χ(2)=8.154, d.f.=1, p=0.004) were significantly different between patients and controls who were apolipoprotein E (APOE) ε4 positive. The T allele and TT+TC genotype were associated with a reduced risk of developing SAD (T allele: odds ratio [OR]=0.541, 95% confidence interval [CI]=0.368-0.859, p=0.005; TT+TC genotype: OR=0.613, 95% CI=0.315-0.725, p=0.012). There was no statistically significant difference in allele and genotype frequencies between patients with SAD and control subjects for the A2M I1000V polymorphism, even after stratification by age of onset, gender, and APOE ε4 status. We found an interaction between LRP1 and APOE genotypes (p=0.001), but no interaction between LRP1 and A2M genotypes. Our results suggest that the T allele of the LRP1 C766T polymorphism is associated with a decreased risk of SAD in APOE ε4 carriers from the Northern Han Chinese population.