15 January 2006. It is touted as only the second genetic variant for late-onset Alzheimer disease. In yesterday’s Nature Genetics online, an international collaboration led by Peter St George-Hyslop at the University of Toronto reports that SORL1 is associated with increased risk for familial late-onset Alzheimer disease (LOAD) in several different ethnic groups. The gene is also known as SORLA (for sortilin-related receptor, low-density lipoprotein receptor class A repeat-containing protein). While SORL1 may not rival ApoE, the leading risk gene for LOAD, the researchers believe that the robustness of SORL1’s association means it may be comparable in importance. In addition, because SORL1 plays a crucial role in amyloid precursor protein (APP) processing, the finding turns the heat up under amyloid-β (Aβ), recently moved to the back burner as researchers searched for other causes of sporadic, or late-onset AD.
It was this biological connection that prompted St George-Hyslop and colleagues to look for a genetic association between SORL1 and AD. Work from Thomas Wilnow’s group at the Max Delbrueck Center for Molecular Medicine in Berlin, Germany, had suggested that the intracellular sorting receptor guides APP away from late endosomes, where the precursor is processed by β- and γ-secretases to generate Aβ (see ARF related news story and Andersen et al., 2005). James Lah at Emory University in Atlanta, Georgia, and colleagues had shown earlier that the level of SORL1 (also know as LR11) is reduced in the brains of people with the disease (see Scherzer et al., 2004). Armed with these clues, Ekaterina Rogaeva and colleagues looked for genetic links between AD, SORL1, and various other vacuolar sorting proteins, including VPS35, VPS26A, sortilin, and the sortilin-related receptors SORCS1-3.
The researchers first screened two independent late-onset FAD data sets (124 northern European FAD families and 228 Caribbean Hispanic FAD families) for intragenic single nucleotide polymorphisms (SNPs) that might be associated with the disease. SNPs in SORL1, SORCS1, and SORCS2 showed an association that was statistically significant, but on further analysis with additional SNPs, only the association with SORL1 remained robust. Alzgene meta-analysis also suggests a slight positive association between SORCS1 and AD. In the January Nature Genetics, Lars Bertram of Massachusetts General Hospital, Charlestown, and colleagues describe how this meta-analysis has identified more than a dozen more potential AD susceptibility genes in addition to ApoE (Alzgene is supported by the Alzforum) (Bertram et al., 2007).
Focusing on SORL1, Rogaeva and colleagues found that six SNPs turned up a positive association in one of the two data sets and also in at least one of four additional data sets used to replicate the analysis. These include case-control samples from northern European and Israeli Arab studies, and Caucasian and African American sibships from the MIRAGE study (hear related presentation from the 9th ICAD meeting). The work was done in collaboration with Lindsay Farrer and colleagues at Boston University School of Medicine and Richard Mayeux at Columbia University, New York.
The SNPs in question cluster at the 5’ and 3’ ends of the SORL1 gene, but not all SNPs are associated with LOAD in all samples tested. At the 5’ end, three SNPs (8-10 in this paper) associate with the disease in the Caribbean Hispanic FAD families and in the Israeli Arab and northern European case-control sample sets. At the 3’ end of the gene, two SNPs (19 and 23) associate with AD in the northern European FAD and case-control sample sets. Haplotype analysis also implicated the three 5’ SNPs, in addition to SNP 11, and two 3’ troikas (SNPs 22-24, and SNPs 23-25) as risk alleles for AD.
To verify the associations, the authors collaborated with Steven Younkin at the Mayo Clinic, Jacksonville, Florida, to analyze yet three different American cohorts of Caucasian European ancestry. Genotyping 10 SORL1 SNPS showed a statistical association between AD and three SNPs (23-25) in one cohort and one SNP (12) in a second cohort. Combined analysis of the three cohorts identified those four and two other risk alleles (SNPs 4 and 19).
All told, the analysis spanned nine data sets and approximately 6,000 individual samples. It represents a major collaborative effort. Statistically significant associations of SORL1 with AD turned up in six of the nine cohorts, while a borderline association was found in a seventh. Unlike ApoE, however, the analysis did not identify one SNP or haplotype that associates with all data sets. That might be revealed by further genotyping, the authors believe. “We don’t think the SNPs that we have used are anything more than simple tags or markers, and we don’t think that they are, themselves, likely to be disease-causing mutations,” said St George-Hyslop in a press briefing. “However, what they do do is identify specific regions of the SORL1 gene likely to be the site where these mutations occur.” The researchers are confident that the disease-causing mutations lie in the SORL1 gene because when they tested SNPs flanking the 5’ and 3’ ends of the gene, they found no association with AD.
Many people will be wondering how this new AD gene stacks up against ApoE as a risk factor and how much of LOAD can be attributed to SORL1 genetic variation. The researchers were reluctant to make that prediction. “It would be prudent for us to first identify the mutation or exact change in the gene that is causing this association,” said Mayeux. Secondly, he pointed out that because the study deliberately focused on families with AD, it is difficult to extrapolate to the general population. “At some point in the future, though, we will be able to go to an elderly population who are unselected for any reason, and determine what the attributable risk will be, once we identify the true variant in the SORL1 gene,” he added.
To find the true disease-causing variation(s), the authors genotyped the exons and intron-exon boundaries in DNA samples positive for the 5’ (SNPs 8-10) and 3’ (SNPS 22-24) haplotypes that associate with AD, but they could not find any pathogenic sequence variations. This leads them to suggest that the disease-causing mutations are likely to be intronic and that they somehow modulate SORL1 expression. In support of this notion, they found that lymphoblasts isolated from AD haplotype carriers express only half as much SORL1 as lymphoblasts from non-carriers.
One strength of the SORL1 association is that it dovetails well with some of the known biology of LOAD, namely the processing of APP. Rogaeva and colleagues found that SORL1 binds to APP in HEK cells and that overexpression of the sorting receptor reduces Aβ production, while underexpression does the opposite. This would suggest that, as in early-onset familial AD, modulation of APP processing may be fundamental to disease etiology in at least some cases of late-onset disease.—Tom Fagan.
Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song Y-Q, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nature Genetics. January 13, 2007. Advanced online publication. Abstract