rs12364988

Family- and cohort-based genetic association study identifying 17 coding mutations in SORL1 associated with late-onset Alzheimer's disease (LOAD) in Caribbean Hispanics. Three variants (rs2298813-A528T, rs117260922-E270K, rs143571823-T947M) segregated significantly within families. Functional studies showed E270K and T947M increase Aβ40 and Aβ42 secretion, while A528T increases Aβ42 secretion (p<0.01), suggesting SORL1 mutations impair APP processing.

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.