Summary: A new study shows variations in a gene called SORL1 are associated with an increased rate of late onset Alzheimer’s. The effect of this gene on your risk of developing the disease is probably modest, and researchers don’t know which variations of the gene could increase that risk. The results of this study will not lead to a simple genetic test for increased risk of Alzheimer’s, at least not anytime soon. But the discovery, along with related research, may generate new ideas for Alzheimer’s treatments.
I’ve been taking a break from blogging about Alzheimer’s and dementia. But when I picked up the newspaper from our driveway Monday morning, the top headline screamed “Gene linked to Alzheimer’s.” “More than 40 scientists worldwide find an inherited flaw that can lead to the disease,” the subtitle said.
I’m tired of headlines announcing Alzheimer’s breakthroughs, but decided to check it out anyway.
The headline referred to a new study that shows variations in a gene called SORL1 are associated with an increased rate of late onset Alzheimer’s. Results of the study, conducted by researchers from fourteen universities and institutes, were published online in the February edition of Nature Genetics.
Despite my skepticism about the headline, this study is intriguing. But it doesn’t mean a simple genetic test can tell you if you’re at increased risk of developing Alzheimer’s, at least not anytime soon.
To understand why the study is important, you have to look at related research results published in the last few years.
SORL1 in the Alzheimer’s Brain
Some of the early clues that SORL1 might be involved in Alzheimer’s came from physiological, rather than genetic, studies. First, scientists found that the level of the protein SORL1 was lower in the brains of people who had late onset Alzheimer’s than it was in “normal” brains.
How is a protein related to genes? The information stored in our genes is used to make proteins. Variations in genes (either inherited or that happen during a person’s lifetime) change how proteins are made. The theory is that variations in the SORL1 gene change how the corresponding protein (also called SORL1) is made, perhaps by regulating levels of the protein.
With the new study, there is now evidence that SORL1 may contribute to the risk of Alzheimer’s on both a physiological and a genetic level.
SORL1 Affects Levels of Beta Amyloid
Dr. James Lah is Assistant Professor of Neurology at Emory University, and co-author of the study linking SORL1 protein levels to Alzheimer's. Last year, he and his colleagues found that decreasing levels of the SORL1 protein increases the amount of beta amyloid near cells in lab tests. Beta amyloid is the sticky protein that makes up the plaques found in the brains of Alzheimer’s patients.
This finding is exciting for researchers who think beta amyloid causes Alzheimer’s, and are working on treatments targeting that protein.
“The available data support an important role for LR11 [SORL1] in AD pathogenesis and identify this receptor as a potential novel therapeutic target for treatment of late-onset sporadic AD,” Dr. Lah and his colleagues wrote in their paper published last year in the Journal of Neuroscience.
SORL1 Is a Receptor for APOE
In addition to the link between SORL1 and beta amyloid, there’s a connection between SORL1 and the APOE gene already known to influence the risk of developing Alzheimer’s. The protein SORL1 is a receptor, which means when a specific molecule is nearby, SORL1 binds itself to that molecule, and then causes a reaction within a cell. The specific molecule it binds to is APOE.
APOE is a kind of protein involved in processing cholesterol and other fats. A variation in the corresponding APOE gene, APOE4, has been linked to Alzheimer’s disease. Given this link, APOE variations change the effect of SORL1 variations on Alzheimer’s risk, or vice versa?
“When we began studying LR11/SorLA our first efforts were directed at finding a relationship between it and APOE,” says Dr. Lah. “Their interactions have been surprisingly elusive. However, in my opinion, it is difficult to believe the functional links are merely coincidental. I expect that further work will define the nature of their interactions at both genetic and physiological levels. With the added attention that will follow the Nature Genetics paper, I expect this will come out pretty quickly.”
Intriguing, But More Research Needed
So, why won’t these discoveries lead to a simple genetic test for increased Alzheimer’s risk anytime soon?
While it’s too early to tell how much the SORL1 gene affects the chances of developing the disease, the co-authors of the new paper write that they believe the effect will be “modest.” There are several reasons for this.
First, SORL1 and APOE are just two of many genes suspected to affect the risk of developing Alzheimer’s. In an article published in the January issue of Nature Genetics, researchers at Massachusetts General listed 13 other “potential Alzheimer disease susceptibility genes.”
Second, scientists involved in the new genetic study couldn’t identify which variations of the SORL1 gene might increase the risk of Alzheimer’s. “In sharp contrast to APOE (where APOE e4 is associated with Alzheimer disease in most data sets), no single SORL1 SNP [common variation] or haplotype is associated with increased risk for Alzheimer disease in all six data sets,” they wrote in the article published this week.
Third, the study didn’t show an association between variations of the gene and increased rates of Alzheimer’s in two of the sample populations studied: Caucasians from the MIRAGE (Multi-Institutional Research in Alzheimer's Genetic Epidemiology) study and another set from the Mayo Clinic in Rochester.
This does not necessarily mean that SORL1 is not a risk factor for the populations the people studied represent. “One possible explanation for lack of association in these data sets is genetic heterogeneity,” says Dr. Lindsay Farrer, one of the study’s authors and Chief of the Genetics Program and Professor of Medicine, Neurology, Genetics and Genomics, Epidemiology, and Biostatistics at Boston University School of Medicine. The problem is that multiple variations in the SORL1 gene may contribute to increased risk. “Specifically, in these samples representing perhaps many ancestral European populations there is no one SORL1 SNP variant or haplotype sufficiently enriched to show an association,” he says.
Dr. Farrer also says perhaps the groups in which no association was found just weren’t big enough, especially given the conservative statistical approach used in this study. It may also be that other causes of Alzheimer’s (genetic or not) were somehow over-represented in these groups.
Despite these uncertainties, the results from this analysis of the genetic material, family relationships and medical histories of over 6000 study participants “suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease,” wrote Dr. Farrer and his colleagues.
The scientists supplemented their genetic findings with research on the physiological level by testing for levels of SORL1 in the blood of participants. Those diagnosed with Alzheimer’s had blood levels of SORL1 less than half that of non-Alzheimer’s participants. But this finding had its own uncertainties: only about 14 percent of that difference was accounted for by SORL1 variations.
They also showed in lab tests that decreasing SORL1 in cells increased the production of beta amyloid. This confirmed the earlier research described above, and the results of these new tests will add detail to the hypothesis about the mechanism by which SORL1 may affect beta amyloid.
Something Dr. Lah said helps clarify the connection between the genetic and physiological research for me. “I believe we are entering a new period in which we will be identifying genetic influences on the common late-onset forms of Alzheimer's which individually modify risk more modestly than the very, very potent effects associated with APOE,” he says. “However, these new findings are likely to shed light on physiological pathways that will lead to development of new and more effective treatments for Alzheimer's disease.”
More study on both genetic and physiological levels is needed. “My co-investigators and I encourage other researchers to evaluate association with SORL1 in other datasets,” says Dr. Farrer. “We predict that many, perhaps most, but not all data sets of reasonably large sample size will demonstrate association with one or more SNPs [common variations]. While confirmation is certainly important, in light of our results in which we could not identify any of the SNPs showing association with AD to be functionally or biologically relevant, more intensive interrogation of other variants in this gene is warranted.”
Dr. Lah is a bit less cautious. “I am admittedly biased,” he says, “but I believe that the SORL1 genetic association will hold up, and that LR11/SorLA in Alzheimer's disease will emerge as an important aspect of the disease.”
Reading through the study again, I realize it’s a good example of why there’s often a disconnect between optimistic Alzheimer’s headlines (which set our expectations too high) and the realities of research. The study is big, hard for a non-scientist to understand, and full of twists and turns. Nothing is simple in Alzheimer’s research. But that isn’t the researchers’ fault. We need to have realistic expectations, and support those who are willing to work in this difficult area. I guess I’ll get back to blogging.