In the complex genetics of Alzheimer’s, only a handful of genes by themselves have a massive impact on risk. ApoE4 and TREM2 boost a person’s odds of late-onset AD from three- to 12-fold, and the three autosomal-dominant genes APP, PS1, and PS2 bring on AD with near certainty. All other AD genes confer much smaller odds. Or so we thought. Growing evidence now suggests that a sixth gene, the endocytic receptor SORL1, deserves a place among this set. Several recent studies have identified pathogenic SORL1 variants that segregate with the disease in families. Now, researchers led by Richard Mayeux at Columbia University in New York report finding 17 rare loss-of-function SORL1 variants in a large whole-exome sequencing study. The variants occurred exclusively in people with cognitive impairment or AD, never in healthy controls. This strengthens the case that they cause disease. AD patients carrying these mutations developed the disease seven years earlier on average than did noncarriers. The findings appeared online May 24 in the Annals of Clinical and Translational Neurology. “This elevates SORL1 to one of the major AD risk genes,” Mayeux said.
- Rare loss-of-function mutations in SORL1 appear to cause AD.
- More common SORL1 missense mutations boost risk as much as ApoE4.
- This makes SORL1 one of the top six AD risk genes.
Other researchers in the field agreed. “There is no longer any doubt SORL1 is a major genetic determinant of Alzheimer's disease, probably by participating in a central pathophysiological pathway,” Jean-Charles Lambert at Institut Pasteur de Lille, France, wrote to Alzforum. SORL1 protein, also known as SORLA or LR 11, shunts amyloid precursor protein (APP) into non-amyloidogenic processing pathways, and loss of SORL1 leads to higher Aβ levels in cell culture experiments. “If this were to be confirmed [in vivo], it would obviously be additional genetic evidence supporting the amyloid cascade hypothesis,” Lambert added (full comment below).
SORL1 first turned up as an AD risk gene in GWAS studies (Rogaeva et al., 2007), and SNPs in or around the gene were found to associate with AD in multiple ethnic groups (Lee et al., 2007). Brain SORL1 levels are low in people with mild cognitive impairment or AD (Scherzer et al., 2004; Dodson et al., 2006; Sager et al., 2007). Meanwhile, a protective SNP boosts SORL1 expression and lowers Aβ in cell culture (Mar 2015 news). The gene was first implicated in familial AD when French geneticists led by Dominic Campion identified SORL1 variants in seven out of 29 families with unexplained early onset AD (Apr 2012 news).
Moving Up? SORL1 belongs near higher-impact variants, not GWAS hits, said Richard Mayeux, who placed a red star in this diagram to estimate an aggregate location for all SORL1 variants. [Image adapted from Manolio et al., 2009.]
For their part, Mayeux and colleagues did not set out to look for SORL1 variants. They were simply searching for some of the missing heritability of AD, i.e., that large fraction of cases that is not accounted for by the genetic variants known to date. First author Neha Raghavan performed an unbiased screen of whole-exome sequencing data from people with AD and healthy controls participating in the Washington Heights-Inwood Community Aging Project (WHICAP) and the Alzheimer’s Disease Sequencing Project (ADSP). WHICAP follows people who are 65 or older and initially free of dementia, while ADSP enrolls cases and controls 60 and older. The authors also added data from 6,395 controls seen at Columbia University, for a total of 6,965 cases and 13,252 controls in the study.
Genetic variants that exert large effects on disease tend to be rare, perhaps because natural selection weeds the most damaging mutations out of the population. For this reason, Raghavan and colleagues focused on ultra-rare coding variants present in the general population in fewer than one person in 10,000. They looked for any loss-of-function mutations that were enriched in cases versus controls. To increase their chance of finding genes, they combined the signal from different loss-of-function variants in the same gene, a technique known as gene-based collapsing analysis.
Using these methods, variants in only one gene—SORL1—achieved exome-wide significance. Nineteen of the AD cases carried such a variant. One control did too, but that person had mild cognitive impairment, suggesting AD might be afoot. Most variants occurred in only one person in the cohort, for a total of 17 different SORL1 loss-of-function mutations.
As in other studies, SORL1 mutations were not confined to a particular ethnicity, appearing equally often in Caucasians, African-Americans, and Caribbean Hispanics. As additional evidence of their pathogenicity, Mayeux noted that these mutations are virtually absent from the genomes of cognitively healthy people, with only one of the 17 appearing in the Exome Aggregation Consortium (ExAC) database, which selects against childhood genetic diseases but not age-related diseases. None of the disease-associated SORL1 variants appeared in the smaller but more stringent Healthy Exome (HEX) database maintained by Alzforum.
Commenters consider the data in this paper to be strong. “This is an exciting paper, which, together with previous studies, clearly motivates further studies on SORL1 as an important player in AD pathogenesis,” Caroline Graff at the Karolinska Institute in Stockholm wrote to Alzforum (full comment below). Håkan Thonberg, also at Karolinska, added that the paper adds evidence for SORL1 being causative for AD.
Mayeux noted that this is the first population-based study to demonstrate a genome-wide association between SORL1 loss-of-function mutations and AD. Previous studies of highly pathogenic mutations focused on families with early onset disease (Verheijen et al., 2016; Thonberg et al., 2017; Gómez-Tortosa et al., 2018). A recent case report describes the first person known to be missing both copies of SORL1. He developed AD at 55, younger than when either of his parents had, though still in the same range as SORL1 heterozygotes (Le Guennec et al., 2018).
Given these findings, should SORL1 be considered autosomal-dominant? Researchers have discussed this question for a while (Aug 2017 news), but told Alzforum they still need to analyze more extensive family trees before they can draw this conclusion. “We don’t know yet if it is 100 percent penetrant,” Mayeux cautioned. Nonetheless, Henne Holstege at VU University Medical Center in Amsterdam believes that more data will ultimately confirm SORL1 as the fourth autosomal-dominant AD gene, with at least some of its mutations being fully penetrant. She compared SORL1 to presenilin 2. Not all of those mutations are fully penetrant, either.
Other SORL1 variants have less severe effects. Some missense mutations, which change a single amino acid, also associate with AD. Mayeux and colleagues reported that SORL1 missense mutations were enriched in cases versus controls in their study, appearing in 1.8 percent of the former and 1 percent of the latter. Other studies have associated specific SORL1 missense mutations with late-onset AD; notably, these variants boosted Aβ levels in cell culture (Cuccaro et al., 2016; Vardarajan et al., 2015). In a family with several ApoE4 homozygote members, inheriting a SORL1 missense mutation in addition to ApoE4 appeared to trigger earlier AD onset and increase the penetrance of ApoE4 (Louwersheimer et al., 2017). Holstege calculated in her recent study that rare, pathogenic SORL1 missense mutations confer about a 12-fold increased risk of AD, similar to ApoE4 homozygosity (Holstege et al., 2017).
In this, SORL1 follows a pattern seen for other GWAS hits, for example ABCA7, noted John Hardy at University College London. With the ABCA7 gene, rare loss-of-function mutations have far stronger effects than the common variants in the same gene found in large association studies. Researchers suspect that more such genes will be found, and help explain the heritability of AD. Some researchers, including Hardy, expressed surprise that Mayeux’s study turned up only SORL1. “It’s interesting that the yield of novel genes was so low,” Hardy wrote (full comment below).
Why did the association between SORL1 and familial AD take such a long time to find? Ideally, scientists want to determine penetrance for each variant in large and informative families. In the case of SORL1, such pedigrees have been hard to come by thus far. But evidence is accumulating. “In clinical files of SORL1 mutation carriers in our clinic, we often see early onset AD in the first and second degree,” Holstege wrote. She added, “Nevertheless, proving that the SORL1 mutation segregates in these families can still be complicated, as not all family members can be approached for genetic testing or, in some cases, hesitate to participate in genetic segregation studies.”
In her recent study, only the rarest SORL1 variants were pathogenic, suggesting they are selected against. “That was surprising to us, given that AD develops after the reproductive phase. Maybe SORL1 also plays a key role earlier in life,” she told Alzforum.
Each individual SORL1 loss-of-function mutation may be rare, but in the aggregate, they account for more AD cases than do presenilin 1 and 2 combined, Holstege said. Her study identified rare, damaging SORL1 mutations in 2 percent of AD cases. Mayeux noted that SORL1 mutations are more common than pathogenic TREM2 variants, as well, though much less common than ApoE4.
Why are some missense variants pathogenic, and others not? Answering this could open a window into SORL1 biology and suggest therapeutic targets, Jessica Young at the University of Washington in Seattle wrote to Alzforum (full comment below). Mayeux is doing such studies now, expressing pathogenic SORL1 variants in cell lines to examine their functional effects. SORL1 forms part of the retromer, a protein-sorting complex, where it helps direct APP from endosomes back to the trans-Golgi network. This transport prevents cleavage of APP into Aβ (Mar 2005 conference news; Sep 2007 news). SORL1 is also believed to route Aβ peptides to the lysosome for degradation (Feb 2014 news). SORL1 GWAS variants were recently linked to higher amyloid PET signals in MCI and dementia (Jan 2018 news).
All of these recent data raise the question of whether, and how, to use SORL1 in clinical practice. Many clinicians are loath to use rare mutations until they are clearly shown to be causal. Thonberg, a clinical geneticist at Karolinska, believes this is warranted. “Caution must still be taken when it comes to using this finding in clinical settings, and our advice is not to use it at all for risk assessment,” he wrote to Alzforum (full comment below).
Now that SORL1 pathogenic mutations have been identified, however, many clinicians report finding them in patients, Holstege said. Several have asked her for guidance on how to treat these patients, but the answer is unclear at present. “What can we offer these patients? Should we make them eligible for enrollment in clinical trials and observational studies like DIAN? We need to start this discussion, because we might find more genes like this,” Holstege suggested.—Madolyn Bowman Rogers
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