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 epsilon4 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.