rs157580

This study examined 4960 SNP triples from five genes in the APOE region (BCAM, NECTIN2, TOMM40, APOE, APOC1) in 2789 Alzheimer's disease cases and 16,334 controls using a novel co-skewness metric to identify complex haplotypes associated with AD. The authors identified 1127 significant AD-associated SNP triples, demonstrating that complex multi-SNP haplotypes—which may not include the canonical APOE ε4 or ε2 alleles—play definitive roles in AD predisposition, with the ε4 allele showing strengthened connections to other region alleles and ε2 showing weakened connections in affected subjects.

A candidate gene association study of dementia risk in 2,857 older postmenopausal women from the Women's Health Initiative Memory Study examining 96 SNPs across five genes (APOE/TOMM40, BDNF, COMT, SORL1, KIBRA). The APOE/TOMM40 locus showed the strongest association (rs157582: OR=1.64, p=2.4×10⁻⁸ for probable dementia), with additional significant associations in COMT (rs737865), BDNF (rs1491850), and KIBRA (rs4320284, rs2241368, rs244904). Results support APOE/TOMM40 as a dementia risk locus and extend associations to COMT, BDNF, and KIBRA genes.

This comprehensive genome-wide association study examined genetic variants contributing to late-onset Alzheimer's disease (AD) in 513 African American cases and 496 controls, plus replication in 5 white cohorts. The APOE ε4 allele showed strong association (P=9.69×10⁻²³), and after adjusting for APOE, rs6859 in PVRL2 remained significantly associated (P=0.0087). The study found associations with variants in CLU, PICALM, BIN1, EPHA1, MS4A, ABCA7, and CD33, though effect directions sometimes differed from white populations. Novel associations with suggestive evidence were identified in PROX1, CNTNAP2, STK24, and other genes, though not replicated in whites.