Early last month the International Genomics of Alzheimer’s Project (IGAP) was launched, with the goal of discovering and mapping genes that contribute to the disease. Four groups from Europe and the United States are participating; one is the Alzheimer’s Disease Genetics Consortium (ADGC), led by Penn’s Gerard Schellenberg, professor of pathology and laboratory medicine.

Identifying those genes “will help lead us to the cause of the disease, identify proteins and other new targets for drug development, and provide genetic methods for determining which people are at greatest risk for Alzheimer’s disease when preventative measures become available,” says Schellenberg, who two years ago received an $18.3 million grant from the National Institute on Aging (NIA) to lead the ADGC’s study to identify what he calls “susceptibility genes.”

Back in 1995, when Schellenberg was at the University of Washington, he discovered a “very virulent” genetic mutation in a group of people known as the Volga Germans, whose ancestors had migrated from Germany to the Volga River region of Russia. The presenilin-2 gene wasn’t just a risk but a direct cause of early-onset Alzheimer’s, he explains. Knowing that his own family were Germans whose ancestors had moved to Russia, he “immediately went home and checked”—and found to his relief that they had migrated to the Black Sea, not the Volga.

His current research involves genes that may contribute to Alzheimer’s risk, which he hopes will not only help identify people who are at risk of getting the disease, but also contribute to a cure.

“Genetics starts you down the pathway of generating knowledge,” which then can be used to explore whether a gene is a good drug target, says Schellenberg. “And it does so in a way that’s not dependent on previous pathways. Some of the drug discovery right now is the path that started with the neurophysiology of Alzheimer’s disease,” namely beta-amyloid plaques and tau tangles.

But finding the genetic mutations that lead to the disease requires casting a wider net than just the tau and beta-amyloid pathways. In recent years that net has been greatly expanded by technological advances such as a genotyping-array chip that allows researchers to “sample all that genetic variability in the human population,” in Schellenberg’s words.

“There are 30,000 genes, and I’m going to let genetics and nature tell me which ones are important for risk,” he says. “I’m trying to generate new bases of knowledge, because so far we don’t have a therapy based on tau, and we don’t have a therapy based on a-beta. So if those don’t work or don’t give us the complete answer, we need new leads.”

Finding a susceptibility gene “tells you that gene and that protein is important for the disease, but it doesn’t tell you how,” he adds. “So the next phase is to actually pursue the function of the risk genes we’re coming up with.”

The fact that 29 Alzheimer’s centers across the country contributed to his most recent genetic study, which has 140 co-authors, makes him “incredibly happy with the way people are working together.” Those findings show that “the more samples you have, the more genes you can identify,” he adds. “And with this international collaboration, we should have over 20,000 cases put together.”

Another example of collaboration was sparked by the NIA directing the centers to use standard measures to evaluate patients and put that information into a central data repository. “My role is to say, ‘Hey, let’s do genetics,” Schellenberg says. “Let’s get the DNA samples for all these people. The data’s already centralized, and we’ll get genetic data and mix it all together.’”

Vivianna Van Deerlin, who directs the molecular pathology lab at HUP, is in charge of some of the genetic testing performed at Penn. She points out that not all of those genes identified as risk factors or disease genes are available for testing in her clinical lab. Some genes are patented, which can limit her clinical lab from using “a particular gene for clinical testing, like presinilin-1 for Alzheimer’s disease.” (The controversial issue of private companies “owning” genes is a subject for another time.)

“We currently have clinical testing for tau and progranulin mutations available,” which are used to confirm research testing results “or for families with a history of frontotemporal lobar degeneration who would like to have a clinical test performed to try to find an answer to their family’s disease,” says Van Deerlin. “For my research lab, which is separate from the clinical lab, our efforts are aimed at collecting a large bank of DNA samples, testing them for known gene mutations, and using the DNA samples for gene discovery.”

After someone with a “strong family history sees one of our collaborating neurologists,” she explains, “we usually first screen for mutations in known genes associated with the disease. We can then make correlations with the clinical data, the biomarker data, the neuropathology data. Together, that information provides a complete picture of the disease, which can be used to improve diagnosis and prognosis, and eventually therapy.”

In order to integrate all that genetic, clinical, biomarker, and neuropathology data, “it was necessary to design a novel integrated database,” Van Deerlin notes. “We hope that this database, which continues to develop and grow, will some day be directly linked to the patient’s medical records to maximize its utility as a research tool.” Even now, their “bank of really well-annotated samples” of DNA, RNA, plasma, and CSF” (cerebrospinal fluid) is linked to extensive clinical and family-history information.

Finally, “while it’s not pleasant to talk about people dying, we have autopsy confirmation for a large number of those who do die of the disease, as well as autopsies of normal controls,” she adds. “Controls are one of the hardest things to get, but also one of the most important—many of our discoveries are enabled by normal individuals dying and contributing their brain.”

According to Beth McCarty Wood, a genetics counselor with the CNDR, Alzheimer’s patients and their families “have become much more interested in genetics” since she began working there seven years ago. “People are really interested in any kind of testing that can better explain why they or their loved one got the condition, as well as determining the risk for other family members to have Alzheimer’s disease or FTD.

“We’re very fortunate that our patients have been highly motivated to help the research center,” she adds. “Genetics can sometimes seem sort of scary. If people don’t understand exactly how the research is being done, it might not be something that they think of getting involved in.”

The knowledge gained from genetics now goes beyond just getting or not getting the disease. Last year, David Wolk, assistant professor of neurology, led a study that broke down the ways that the APOE-e4 gene, a known risk factor for Alzheimer’s, affects patients with even mild forms of the disease. Those who had that form of the gene performed worse on memory tests and had more prominent abnormalities in brain regions critical for memory than those who didn’t. But those with mild Alzheimer’s who didn’t have that variant performed worse on tests of attention, language, and executive function, a result borne out by more prominent abnormalities in the brain regions critical for those abilities.

Once preventative options are available, “the whole field of genetics and neurodegenerative conditions will be greatly impacted,” says Wood. “Right now, if someone knows they’re at risk for a gene mutation that causes the disease, the only reason to get tested is for [their] own personal reasons, whether it’s making decisions about children or about retiring. But once there’s a medical option we can give them, to delay progression of the disease or to prevent the disease entirely, we’re going to see many more people wanting to have genetic testing to determine their risk.”—S.H.

 


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COVER STORY: Untangling Alzheimer's By Samuel Hughes
©2011 The Pennsylvania Gazette

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The Ethics of Alzheimer’s

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Genetic Dragnet


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