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Late-onset Gene for AD Confirms the Role of Amyloid in Disease

An association between the neuronal sortilin-related receptor (SORL1) gene and late-onset Alzheimer disease, reported in the journal Nature Genetics, appears to add yet more weight to the centrality of amyloid in the pathogenesis of Alzheimer disease (AD).

Moreover, the report — which confirms other studies implicating SORL1 and its role in the intracellular generation of amyloid beta peptide — replicates the association across several different cohorts and ethnic populations.

The finding was reported by Peter St. George-Hyslop, PhD, of the Centre for Research in Neurodegenerative Diseases at the University of Toronto, and colleagues at multiple clinical research centers in the US, Europe, Israel and elsewhere; it appeared in the Jan. 14 online edition of Nature Genetics.

“The recycling of the amyloid precursor protein from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide in Alzheimer disease,” the researchers state in the Nature Genetics report. “…Inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease.”

They add that SORL1 directs trafficking of the amyloid precursor protein (APP) and that “when SORL1 is underexpressed, APP is sorted into amyloid-beta-generating compartments.”

A Relatively Rare Mutation

But some AD experts caution that the widespread publicity afforded the SORL1 finding in the lay press may have obscured the fact that the effect of SORLS 1 as a genetic risk factor for AD is far from robust.

Rudy Tanzi, PhD, professor of neurology at Harvard Medical School, noted that of all the SORL1 single nucleotide polymorphisms (SNPs) tested by the group, the one associated with the highest risk for disease only increased risk by 21 percent; other SORL1 SNPs increased risk by ten percent or lower.

“In terms of its effect on risk, it is relatively tiny,” Dr. Tanzi told Neurology Today. He is also director of the genetics and aging research unit of the Massachusetts Institute for Neurodegenerative Disease.

In contrast, Dr. Tanzi noted, one copy of the apolipoprotein-E4 (APOE4) gene variant increases risk for disease by about 300 percent and two copies by over 1,000 percent.

Dr. Tanzi cited the AlzGene Web site (www.alzgene.org) maintained by colleague Lars Bertram, MD, which provides a comprehensive catalogue of genetic association studies performed on Alzheimer disease phenotypes, and it ranks the genes according to their risk. (Dr. Bertram is assistant professor of neurology at the genetics and aging research unit in the department of neurology at Massachusetts General Hospital.)

Of 26 genes on the list rank ordered by effects on AD risk, SORL1 is 18th; APOE is number one.

REPLICATION ACROSS DIFFERENT POPULATIONS

But Dr. Tanzi echoed other researchers in acknowledging that a unique strength of the Nature Genetics report is its replication across multiple groups and ethnic populations. “To the credit of the authors, they tested many variants of the gene in many different samples,” he said.

“Finding new genes and new risk factors for AD has been frustrating in part because often one group will report something and four others will report that they can't confirm it,” said Sam Gandy, MD, PhD, director of the Farber Institute for Neurological Sciences at Thomas Jefferson University in Philadelphia, and chair of the medical and scientific advisory council at the Alzheimer's Association.

“Here they have already tested different ethnic populations independently,” Dr. Gandy told Neurology Today.

Others also hailed the report. “This is an excellent study adding another piece to the puzzle of the genetics of Alzheimer disease,” agreed Thomas Bird, MD, chief of the division of neurogenetics at the University of Washington. “It's a careful study and they got a positive finding when they replicated it in several different populations and widely different ethnic groups. Most studies don't do that, so that's a relative strength,” he said.

He noted that the study found a positive association for the gene among African-Americans, Israeli Arabs, and people from the Dominican Republic.

ROLE IN BIOLOGY OF AD

Drs. Bird, Tanzi, and Gandy also agreed that apart from its genetic contribution to risk for disease, SORL1 is clearly implicated in the biology of AD, as confirmed in the paper by St. George-Hyslop and colleagues.

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Dr. Thomas Bird: “This is an excellent study adding another piece to the puzzle of the genetics of Alzheimer disease. … they got a positive finding when they replicated it in several different populations and widely different ethnic groups. Most studies dont do that, so thats a relative strength.”

Dr. Gandy explained that SORL1 plays a role in the intra-cellular trafficking of APP, the parent protein of the amyloid beta (ABeta) peptide, now almost universally recognized as critical in the formation of the distinctive amyloid plaques of AD.

“Their finding fits well with the most mature hypothesis for the pathogenesis of AD, which has to do with the role of amyloid,” he said. The amyloid protein that builds up and forms plaques is a breakdown product of the precursor amyloid protein. Within the cell, the APP parent protein can be directed to two different parts of the cell. At one destination the APP is broken down into innocuous fragments, at another destination it forms amyloid.

“In 2004, Jim Lah and Allan Levey, both neurologists at Emory, made the first association of SORL1 with AD in a paper in Archives of Neurology, showing that SORL1 levels are low in the human AD brain,” Dr. Gandy added. “Their seminal observation is now given much greater import by the SORL1 gene linkage, but Lah and Levey's contribution has been under-recognized because they used the name LR11, an alternate name for SORL1. Only protein sorting cognoscenti recognize that Hyslop's SORL1 and Lah and Levey's LR11 are one and the same.”

“The higher the level of SORL1 the more APP is directed into the good pathway,” Dr. Gandy said. “If there is a deficiency of SORL1, APP is more likely to be broken down into amyloid.”

For that reason, he said, the SORL1 finding could have clinical implications. “We know that elevating SORL1 expression lowers generation of amyloid,” he said. “So we could begin testing existing compounds that are already available to elevate SORL1 or begin looking for new compounds, and the screening could begin immediately.”

Dr. Bird agreed. “Everyone agrees amyloid is the critical player in Alzheimer disease,” he said. “Here is evidence that SORL1 is involved in the movement of proteins within the cell that could direct APP toward the creation of amyloid. That makes it really interesting.”

Dr. Tanzi expressed some skepticism about the clinical feasibility of manipulating SORL1 levels for the purposes of preventing amyloid development.

“The gene does play a role in trafficking of APP from inside the cell to the cell surface, and you can indeed affect the rate at which Abeta is made from APP by manipulating levels of SORL1,” he said. “The problem with that is that SORL1 is a trafficking gene for thousands of proteins. It's part of the machinery inside the cell that transports new proteins as they mature to the cell surface.”

Figure

Dr. Sam Gandy: “Finding new genes and new risk factors for AD has been frustrating in part because often one group will report something and four others will report that they cant confirm it.”

So manipulating levels of SORL1 is likely to result in an intracellular “traffic jam,” Dr. Tanzi said. “To me it's not feasible to talk about modulating something as basic as a trafficking protein,” he told Neurology Today.

Dr. Tanzi added that the testing of candidate genes, one by one, has tended to yield genes conferring a relatively low risk. More promising, he said, are the prospects for unbiased screening of the entire genome using gene chips; that method would more likely yield the genetic “heavy hitters,” he said.

In the meantime, Dr. Tanzi acknowledged that the SORL1 finding is a step forward, and that the media exposure to the Nature Genetics paper could only raise the profile of SORL1. “By getting so much media splash it has made scientists aware of the gene,” he said.

And Dr. Gandy said that though the SORL1 finding would not have a big impact on genetic prediction of AD, it reinforces confidence in the amyloid hypothesis. And he noted that anti-amyloid agents are now entering phase III clinical trials.

“We feel more confident about amyloid and it gets us a new target which is always useful since you can never predict side effects,” Dr. Gandy said.

ARTICLE IN BRIEF

A candidate gene for late-onset Alzheimer disease was identified among several different ethnic groups, and experts say it confirms the role of amyloid in the pathogenesis of the disease

REFERENCES

Rogaeva E, Meng St George-Hyslop P, et al.The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 2007;E-pub 2007 Jan 14.
    Scherzer CR, Offe K, Lah JJ, et al. Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol 2004;61(8):1200–1205.