ARTICLE IN BRIEF
An international consortium of researchers conducted a meta-analysis of gene screenings — in two stages — confirming known genes implicated in Alzheimer's disease and identifying 11 new gene loci associated with the disease. The new variants point to new pathways, and possible therapeutic targets.
The recent discovery of 11 new gene locations involved with the development of Alzheimer's disease (AD) made international news. But researchers said knowing the exact cause — and what to target for a cure — is not close at hand.
There is no denying that the study is cause for celebration, they said. The study confirmed the role of genes discovered earlier and emphasized the role of particular regions associated with the immune system and inflammation. The study also identified new pathways underlying Alzheimer's disease, including those that involve hippocampal synaptic function, cytoskeletal function and axonal transport, regulation of gene expression and post-translational modification of proteins, and microglial and myeloid cell function.
Scientists from more than a dozen countries and more than 40 institutions collaborated on the analysis, the largest international study on AD ever. The paper, which was published in the Oct. 27 edition of Nature Genetics, focused on late-onset AD.
In stage one, the investigators used genotyped and imputed data from 7,055,881 single-nucleotide polymorphisms (SNPs) to perform a meta-analysis on four previously published datasets consisting of 17,008 AD cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for associations in an independent set of 8,572 AD cases and 11,312 controls. Nineteen loci reached genome-wide significance and 11 were newly associated with Alzheimer's disease. [See “Eleven New Genes: Alzheimer's Disease” for more information on their function.]
One of the investigators, Oscar L. Lopez, MD, professor of neurology at the University of Pittsburgh, said the study will help researchers to focus on specific metabolic pathways involved with the possible etiology of AD.
“Genetic studies are showing us three big areas to focus on — the immune system, the lipid and cholesterol metabolism, and the amyloid protein production that helps the neurons move protein from one cell to another.”
According to the study, beyond the already known genome-wide association study-defined genes, the most significant new association was in the HLA-DRB5–DRB1 region. This region is also related to risk of both multiple sclerosis and Parkinson's disease.
“There are several major successes in this study,” said Thomas D. Bird, MD, a research neurologist at the Seattle VA Medical Center and chief of the Division of Neurogenetics at the University of Washington, who was not involved with the study.
“The first is that this is a real tour de force because of the numbers of subjects and controls — you have thousands of people gathered here and that's really impressive.
“The second is that there is always this yin and yang for a practicing clinical neurologist. While there isn't anything that you can use in the clinic for diagnosing Alzheimer's disease, it's an important piece in confirming and identifying previously recognized pathways and pointing out new pathways in which pathogens might assist with the disease.
“Finally, by developing ideas of how the disease is initiated, down the line we can focus on those places to interrupt the disease therapeutically,” said Dr. Bird, who serves on the editorial advisory board of Neurology Today.
Now that new loci have been identified, researchers still need to determine the amount of risk the genes contribute. It could be that they only contribute to 3 or 4 percent of the population, said David Gill, MD, a behavioral neurologist at Unity Rehabilitation and Neurology and clinical assistant professor at the University of Rochester Medical Center.
Dr. Gill said the study added evidence, both in supporting previous work and targeting potential causal pathways. But it's unclear how the 11 genes are involved and if they increase or decrease the risk.
“The genes that were found may be involved in cholesterol movement of particles in the cell within the immune system, which we know are involved in Alzheimer's, but we don't know how,” said Dr. Gill. “For us to say that the immune system is more involved, I don't know if that's fair to say, but the study provides added evidence.”
Part of the blessing and the curse of studying Alzheimer's disease is that there are so many proteins that are involved.
“It's almost an embarrassment of riches,” said Dr. Bird. “But with so many targets, it's difficult to know where to start and how to interact with the system. Do you start with inflammation? Lipid transport? Amyloid production?”
“It is clear that the clinical Alzheimer's phenotype is way more complex than we have been assuming,” said Sam Gandy, MD, PhD, director of the Mount Sinai Center for Cognitive Health and the Mount Sinai chair in Alzheimer's disease research.
“While hoping that single agent/single target prevention will have a meaningful benefit, I am more and more worried that this will turn out to have been quite naive when we look back 10 years from now.”
Dr. Gandy noted that the prevention trials are all focused on amyloid although there are recent revelations that up to one third of the clinical AD cases have negative amyloid scans. He pointed out that Clifford Jack Jr., a professor of radiology at the Mayo Clinic in Rochester, MN, and colleagues have proposed two types of AD based on imaging: amyloid first or neurodegeneration first; the paper was published in an Oct. 16 online edition of Neurology.
“The idea that neurodegeneration can ever be first represents a seismic shift in formulation of pathogenesis for researchers in the amyloidosis area,” said Dr. Gandy.
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IMPLICATIONS FOR TREATMENT?
The neurologists said that the meta-analysis has no impact on genetic screening at the moment or any treatment implications.
“These studies are giving us some clues that can be used to target in future primary or secondary prevention treatments,” said Dr. Lopez. “That's where the whole thing is going. At the end of the day, we want these studies to allow us to design treatments that help people not develop the disease.”
There is some concern that the public might interpret news about these types of meta-analyses as possible causes and cures for AD.
“I get questions from people and they get frustrated that there is no answer, because they heard some story about genetic tests for Alzheimer's,” said Dr. Gill. “There is no testing that should be done for late-onset Alzheimer's and this study doesn't change that. Even if I did make a diagnosis, it wouldn't change the treatment.”
“Sometimes there's an overenthusiastic response to research, and the public thinks — there are new genes, so soon we'll have a new treatment,” he continued. “And then nothing happens. The general population is getting frustrated.”
But others are a bit more sanguine about the prospects. “Look how long it took to treat hypertension,” said Dr. Lopez. “In the 1960s, there was one drug. Now, 60 years later, there are so many treatments. The field for the study and treatment of Alzheimer's disease started in the late 80s and early 90s.”
LINK UP FOR MORE INFORMATION:
•. Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 2013; E-pub 2013 Oct. 27.
•. Jack CR Jr, Wiste HJ, Weigand SD, et al. Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity. Neurology 2013; E-pub 2013 Oct. 16.
•. Neurology archive on Alzheimer's genetic studies: bit.ly/17UttAv.