Background: Alzheimer disease is thought to be a multi-factorial disease, probably caused by complicated interactions between genetic and environmental factors. To date, only the e4 allele of the apolipoprotein E gene (APOE) is a well-characterized genetic risk factor for late-onset Alzheimer disease (LOAD). Recent genome-wide association studies have reconfirmed that an APOE linkage disequilibrium (LD) locus is strongly associated with LOAD. Nevertheless, there have been a few studies involving genetic association and LD analyses of in and around the APOE. Methods: To identify a novel single nucleotide polymorphism (SNP) in and around the APOE associated with LOAD, we carried out a high-density SNP-based case-control association study in Japanese (LOAD, 547; control, 715). We selected 271 SNPs (mean intermaker distance, 0.77 kb) about 200 kb (49.988 50.188 Mb) on chromosome 19, of which region includes the nine genes, CBLC, BCAM, PVRL2, APOC1, TOMM40, APOE, APOC4, APOC2 and CLPTM1. Fine LD mapping and estimation of recombination hotspots were also performed to clarify the genetic structure in this region. Results: One hundred seventy-one SNPs were actually polymorphic with minor allele frequency 0.01 and did not show significant deviation from the HWE (P-value 0.01) in the Japanese population. Among them, 36 of these SNPs exhibited significance on case-control association study after adjustment for multiple testing. These SNPs are located in a genomic region including four genes, PVRL2, TOMM40, APOE and APOC1. Recombination rate estimation revealed that the associated region is firmly sandwiched between two recombination hotspots. Strong LD between these SNPs was observed (mean jD’j 1⁄4 0.914). Conclusions: We found three additional genes, PVRL2, TOMM40 and APOC1, exhibited significant association with LOAD. By means of only genetic approaches, it is difficult to determine which gene in the associated region is the most likely disease susceptibility to development of LOAD. These data suggest that the three genes other than APOE, i.e. PVRL2, TOMM40 and APOC1, could also yield a predisposition to LOAD.