Late-onset Alzheimer's disease (AD) is a genetically heterogeneous neurodegenerative disorder. In addition to the apolipoprotein E (APOE) gene on chromosome 19, linkage studies suggest the existence of multiple susceptibility genes for late-onset AD. Genome-wide linkage and chromosome-12-specific linkage studies have identified a broad 50-cM pericentromeric region between 12p12 and 12q13 among non- APOE*4 carriers. Some studies have implicated the alpha2-macroglobulin (A2M) gene in 12p12 as being the chromosome 12 gene, but the results are equivocal. Because of its close proximity to the A2M gene and because it is abundantly expressed in the brain, we reasoned that the oxidized LDL-receptor 1 (OLR1) gene could be a candidate gene for AD. We screened all exons and intron-exon boundaries of the OLR1 gene for new mutations and identified three novel sequence variations in intron 4, intron 5, and the 3' untranslated region (UTR). Pair-wise comparisons between the three polymorphic sites revealed significant linkage disequilibrium ( P<0.0001). We screened more than 800 late-onset AD cases and more than 700 controls for the three OLR1 polymorphisms. All polymorphisms showed significant association with AD after stratification by APOE*4, with the strongest effect being observed for the 3'UTR polymorphism among non- APOE*4 (odds ratio 0.658; 95% confidence interval: 0.47-0.92; P=0.014) and APOE*4 (odds ratio 1.72; 95% confidence interval: 1.07-2.78; P=0.025) carriers. DNA-protein binding assay with nuclear protein extracts from neuroblastoma cells indicated that the OLR1/3'UTR polymorphism affects the binding of a transcription factor in an allele-dependent manner. Our data suggest that genetic variation in the OLR1 gene may modify the risk of AD in an APOE*4-dependent fashion.