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

Abstract

To investigate the association of genetic variants in sortilin-related receptor (SORL1), which has been proposed as an important genetic contributor to lateonset Alzheimer disease (LOAD). Design: We analyzed 13 SORL1 single-nucleotide polymorphisms (SNPs) and the relative haplotypes in a casecontrol 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 ε4 noncarriers. Several haplotypic associations at the 5Ј 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.

Sex differences in the genetic architecture of cognitive resilience to Alzheimer’s disease

“…Multiple groups have shown that SORL1 may exhibit sex-specificity, including evidence showing SORL1 variants to be detrimental in females. 71–73 This aligns with what we observed in our study, as we saw a negative association with resilience at a SORL1 variant in females but a positive association in males. In addition, prior evidence suggests sex-specificity at the PICALM locus.…”

Sex differences in the genetic architecture of cognitive resilience to Alzheimer’s disease

“…Multiple groups have shown that SORL1 may exhibit sex-specificity, including evidence showing SORL1 variants to be detrimental in females. 71–73 This aligns with what we observed in our study, as we saw a negative association with resilience at a SORL1 variant in females but a positive association in males. In addition, prior evidence suggests sex-specificity at the PICALM locus.…”

Genetics of Late‐Onset Alzheimer′s Disease: Update from the Alzgene Database and Analysis of Shared Pathways

“…The best one is rs2282649 ( N minor = 1,734 OR 1.10 95% CI: 1.02–1.17). A recent study has suggested that the role of SORL1 as a LOAD gene might be gender dependent, consistently demonstrated in women [67]. We confirmed this result in a sample of AD patients attending our center in Athens.…”

Impact of SORL1 Single Nucleotide Polymorphisms on Alzheimer’s Disease Cerebrospinal Fluid Markers

“…Our analysis revealed that gender influenced the levels of A ␤ 1-42 in the AD group. This finding is in line with the previously reported association between SORL1 gene variants and gender [13] and with reports from AD transgenic animal models indicating an impact of gender on amyloid pathology [34] Secondly, our study was restricted to individuals with a non-Hispanic Caucasian ancestry, whereas the Swedish Twin Registry Study comprised individuals drawn from the multiethnic Swedish society regardless of their origin. A recent meta-analysis on the association between variants in SORL1 and AD showed clear deviations in the AD associated SORL1 SNPs in the different ethnic groups [20] Thirdly, in the referenced ADNI study [30] , patients with probable AD and MCI as well as healthy controls were treated as a single group, and no separate analyses were performed in each of the three groups.…”

Sex differences in the genetic architecture of cognitive resilience to Alzheimer’s disease

“…Multiple groups have shown that SORL1 may exhibit sex-specificity, including evidence showing SORL1 variants to be detrimental in females. 71–73 This aligns with what we observed in our study, as we saw a negative association with resilience at a SORL1 variant in females but a positive association in males. In addition, prior evidence suggests sex-specificity at the PICALM locus.…”

Genetics of Late‐Onset Alzheimer′s Disease: Update from the Alzgene Database and Analysis of Shared Pathways

“…The best one is rs2282649 ( N minor = 1,734 OR 1.10 95% CI: 1.02–1.17). A recent study has suggested that the role of SORL1 as a LOAD gene might be gender dependent, consistently demonstrated in women [67]. We confirmed this result in a sample of AD patients attending our center in Athens.…”

Impact of SORL1 Single Nucleotide Polymorphisms on Alzheimer’s Disease Cerebrospinal Fluid Markers

“…Our analysis revealed that gender influenced the levels of A ␤ 1-42 in the AD group. This finding is in line with the previously reported association between SORL1 gene variants and gender [13] and with reports from AD transgenic animal models indicating an impact of gender on amyloid pathology [34] Secondly, our study was restricted to individuals with a non-Hispanic Caucasian ancestry, whereas the Swedish Twin Registry Study comprised individuals drawn from the multiethnic Swedish society regardless of their origin. A recent meta-analysis on the association between variants in SORL1 and AD showed clear deviations in the AD associated SORL1 SNPs in the different ethnic groups [20] Thirdly, in the referenced ADNI study [30] , patients with probable AD and MCI as well as healthy controls were treated as a single group, and no separate analyses were performed in each of the three groups.…”

Sex differences in the genetic architecture of cognitive resilience to Alzheimer’s disease

“…Multiple groups have shown that SORL1 may exhibit sex-specificity, including evidence showing SORL1 variants to be detrimental in females. 71–73 This aligns with what we observed in our study, as we saw a negative association with resilience at a SORL1 variant in females but a positive association in males. In addition, prior evidence suggests sex-specificity at the PICALM locus.…”

Genetics of Late‐Onset Alzheimer′s Disease: Update from the Alzgene Database and Analysis of Shared Pathways

“…The best one is rs2282649 ( N minor = 1,734 OR 1.10 95% CI: 1.02–1.17). A recent study has suggested that the role of SORL1 as a LOAD gene might be gender dependent, consistently demonstrated in women [67]. We confirmed this result in a sample of AD patients attending our center in Athens.…”

Impact of SORL1 Single Nucleotide Polymorphisms on Alzheimer’s Disease Cerebrospinal Fluid Markers

“…Our analysis revealed that gender influenced the levels of A ␤ 1-42 in the AD group. This finding is in line with the previously reported association between SORL1 gene variants and gender [13] and with reports from AD transgenic animal models indicating an impact of gender on amyloid pathology [34] Secondly, our study was restricted to individuals with a non-Hispanic Caucasian ancestry, whereas the Swedish Twin Registry Study comprised individuals drawn from the multiethnic Swedish society regardless of their origin. A recent meta-analysis on the association between variants in SORL1 and AD showed clear deviations in the AD associated SORL1 SNPs in the different ethnic groups [20] Thirdly, in the referenced ADNI study [30] , patients with probable AD and MCI as well as healthy controls were treated as a single group, and no separate analyses were performed in each of the three groups.…”