rs668387

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 case-control association study of 251 Italian late-onset Alzheimer disease (LOAD) patients and 358 controls identified three SORL1 SNPs (rs661057, rs12364988, rs641120) significantly associated with LOAD (P=0.002, 0.007, 0.03 respectively), with effect sizes (OR) ranging from 1.27-1.7. The associations were stronger in women and primarily confined to APOE ε4 noncarriers, suggesting SORL1 may influence LOAD through a female-specific mechanism independent of APOE status.

This family-based association study examined SORL1 genetic variants previously associated with Alzheimer disease in relation to brain MRI measures of atrophy and vascular disease, as well as neuropathological markers of neurodegeneration. Multiple SORL1 SNPs (rs8-10, rs22-25) and haplotypes showed significant associations with white matter hyperintensities (p=0.001-0.006) and cerebrovascular disease (p=0.002-0.006), demonstrating that distinct genomic regions of SORL1 influence different aspects of AD-related pathology.