Implication of Sex and SORL1 Variants in Italian Patients With Alzheimer Disease

Objective: To investigate the association of genetic variants in sortilin-related receptor (SORL1), which has been proposed as an important genetic contributor to late-onset Alzheimer disease (LOAD). Design: We analyzed 13 SORL1 single-nucleotide polymorphisms (SNPs) and the relative haplotypes in a case-control association study. Participants: The sample included 708 Italian subjects: 251 unrelated, sporadic patients with LOAD, 99 sporadic patients with early-onset Alzheimer disease (AD), and 358 healthy controls. Main Outcome Measures: We analyzed the 13 SNPs in the SORL1 gene that had been studied in previous reports using case-control methods and included sex, apolipoprotein E (APOE) genotype, and age at AD onset as covariates. Results: The SNPs 4 (rs661057), 7 (rs12364988), and 10 (rs641120) were significantly associated with LOAD compared with controls. We found an association between these 3 variants and sex, suggesting that SORL1 may possibly affect LOAD through a female-specific mechanism. Of interest, the association of these SNPs with LOAD was confined to APOE epsilon 4 noncarriers. Several haplotypic associations at the 5' end of SORL1 were found, including the previously associated CGC haplotype at SNPs 8 through 10. Conclusions: Our results confirm the association of SORL1 with AD and show a possible effect of female sex, suggesting that this gene may be a promising susceptibility factor for LOAD. Further studies to detect pathogenic variants and further elucidate the effect of SORL1 on the development of AD are necessary.