The genetic secrets of Alzheimer’s disease are hiding in our DNA. Researchers at Indiana University School of Medicine and colleagues across the country are mounting a revolutionary new research project to find them.
The new national initiative to research the genetics of Alzheimer’s disease, announced July 2, could have a dramatic impact on the development of treatments for the disease, said Indiana University School of Medicine researchers involved in the project.
With funding from the BrinWojcicki Foundation and the Alzheimer’s Association, scientists will sequence and study the entire genomes of more than 800 older adults currently participating in the Alzheimer’s Disease Neuroimaging Initiative. The project will provide a listing of all 3 billion segments, called base pairs, of genetic code in each participant’s DNA.
“This is the equivalent of going from a good quality map of the Unites States to having the detailed blueprints for everything within our borders,” said Andrew Saykin, Psy.D., director of the Indiana University Center for Neuroimaging and principal investigator for the genetics core of the Alzheimer’s Disease Neuroimaging Initiative.
The ADNI is a long-term national research project begun in 2004 to combine genetic information; measures of memory and cognition; data from state-of-the-art brain scans; and biomarkers from blood and cerebral spinal fluid samples to find biomarkers that could lead to new therapies for the disease. The participants include patients diagnosed with Alzheimer’s; people with mild cognitive impairment and therefore considered at risk of developing Alzheimer’s; and people without symptoms who serve as normal controls.
In addition to Dr. Saykin’s leadership of the genetic core of the Alzheimer’s Disease Neuroimaging Initiative, the National Cell Repository for Alzheimer’s Disease at the IU School of Medicine serves as the storage site for the DNA samples collected around the country for the initiative. The repository, directed by Tatiana Foroud, Ph.D., P. Michael Conneally Professor of Medical and Molecular Genetics, prepared the DNA samples that will be used for the new whole genome project. Dr. Foroud and Li Shen, Ph.D., computer scientist and assistant professor of radiology and imaging sciences, are co-principal investigators for the genetics core.
The sequencing will be conducted by Illumina, a biotechnology equipment and services company in San Diego, Calif.
“This whole genome sequencing project should give us important new insights into the origins and processes of Alzheimer’s disease, helping us develop new treatments and hopefully new preventive therapies,” said Martin Farlow, M.D., professor of neurology and associate director of the Indiana Alzheimer Disease Center. Dr. Farlow leads the IU ADNI clinical site and provides clinical services to Alzheimer’s patients at IU. He conducts clinical trials of many potential new Alzheimer’s therapies.
Although the ADNI has produced vast quantities of information that have been used productively by scientists around the world, the new project will provide next-generation sequencing data on a massively larger and yet much more refined scale, Dr. Saykin said. “We will have a new ability to detect novel genetic variations related to what we see on brain scans and to other biomarkers, and this is likely to be important for understanding Alzheimer’s during its critical early stages,” he said.
“We believe that as much as 80 percent of the risk of Alzheimer’s is inherited. But we can’t explain nearly that much with our current slate of established candidate genes,” said Dr. Saykin, Raymond C. Beeler Professor of Radiology and Imaging Sciences.
A team of researchers led by Dr. Saykin reported in December 2010 it had found a new suspected Alzheimer’s-related gene after conducting a genome-wide analysis of potential biomarkers for early detection of Alzheimer’s disease. That study used cerebrospinal fluid samples from 374 participants in the Alzheimer’s Disease Neuroimaging Initiative.
However, that study, using then-new technology that could test about 500,000 genetic markers for a possible link to Alzheimer’s, could only evaluate a sample of common variations that occur in at least 1 percent of the population.
By sequencing the entire genetic code for each of the ADNI participants, researchers will be able to dive deeper into the molecular level to look for rare variations within genes that play as-yet-unknown roles in Alzheimer’s disease.
“This is collaborative team science at its best. Multiple investigators with complementary expertise from many institutions are working together to better understand the molecular causes of Alzheimer’s disease and to improve patient care,” Dr. Saykin said.
“We believe this cutting-edge study will yield important new data that will help in our understanding of the genetics of not only Alzheimer’s disease but perhaps even more importantly mild cognitive impairment, which may lead to Alzheimer’s disease,” Dr. Foroud said.
Alzheimer’s disease and other dementias are among the areas of focus of both the Indiana University Health Neurosciences Center and the Strategic Research Initiative, two research and clinical care collaborations between the IU School of Medicine and Indiana University Health. An estimated 5.4 million Americans are living with Alzheimer’s disease, an illness that has thus far resisted discovery of effective treatments.
The Alzheimer’s Disease Neuroimaging Initiative is led by Principal Investigator Michael W. Weiner, M.D., of the University of California San Francisco and the VA Medical Center, San Francisco. Robert C. Green, M.D., M.P.H., of Brigham and Women’s Hospital and Harvard Medical School, Dr. Saykin and Arthur Toga, Ph.D., of UCLA will lead the coordination of the sequencing efforts within ADNI.