Association of SORL1 Gene Variants with Hippocampal and Cerebral Atrophy and Alzheimer's Disease

Background: Sortilin-related receptor, Sorl1, is a neuronal receptor that interacts with the amyloid precursor protein to regulate amyloidogenesis. Variants in the gene encoding Sorl1 are associated with Alzheimer's disease (AD), as well as its neuroimaging markers. Objectives: To investigate the relationship between SORL1 gene variants with AD-related brain morphologies and AD, testing for sex-specific effects. Methods: The sample comprised 292 individuals aged >= 75 years participating in the longitudinal Sydney Older Persons Study. A sub-sample also underwent a brain MRI scan (n= 102, 53 males; 49 females). The relationships of three SORL1 single nucleotide polymorphisms (SNPs): rs4935774, rs2298813, rs1133174 with brain MRI measures, and AD were determined. Results: Significant associations of SORL1 variants with cross-sectional brain MRI measures and AD were observed only when the sample was stratified by sex. The most common haplotype (H1), comprising rs4935774-T, rs2298813-G, and rs1133174-G alleles (T/G/G) was associated with whole brain atrophy in both males and females (p=0.012 & p=0.013; respectively). Only SNP rs1133174 was individually associated with hippocampal atrophy in males (p= 0.039) and females (p=0.025). Of the 292 participants, 111 had either probable or possible AD. A significant association of H1 with AD (p = 0.017) was observed in females. A nominally significant association of SNP rs1133174 with AD (p = 0.051) was also observed in the whole cohort. Conclusion: The results provide evidence that the association of polymophisms in the sortilin-related receptor gene (SORL1) with AD and its MRI biomarkers of brain and hippocampal atrophy are moderated by sex.