Genome Sequencing Set to Hunt for Alzheimer's Clues

Abstract

T he largest genome-sequencing project ever is the newest weapon against Alzheimer’s. The project will examine the genetic codes of more than 800 people, generating more than 165 terabytes – 165,000 gigabytes – of new information about Alzheimer’s disease and its genetic roots. “This is the biggest single whole-genome scan that has ever been done in any disease, and in one of the best-characterized research cohorts ever seen,” said William Thies, PhD. “We are bound to discover new things.” Improvements in both technology and cost make the project feasible for the fi rst time. The genome sequencing will take about 16 weeks from start to fi nish, said Dr. Thies, chief medical and scientifi c offi cer of the Alzheimer’s Association. The project’s price tag is $2 million ($1 million each from the Alzheimer’s Association and the nonprofi t Brin Wojcicki Foundation). The project is an off shoot of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Dr. Thies said in an interview. ADNI is a global eff ort to improve ways of identifying the best patients for clinical trials by using brain imaging and other biomarkers. The North American section of ADNI has a pool of 800 patients who have been followed since 2004. The cohort “has been characterized to an extent that is almost unheard of in genetic studies,” Dr. Thies said. Upon enrollment, subjects are stratifi ed as having normal cognition, mild cognitive impairment, or Alzheimer’s disease. Close follow-up allows researchers to identifying cognitive and physiological changes as they occur, as well as risk factors that predispose people to disease. Three genetic markers for familial (or early-onset) Alzheimer’s have been discovered so far: mutations in the genes for presenilin-1 and -2 and the amyloid precursor protein. The e4 allele of the gene for apolipoprotein E is known to have the greatest impact on risk for sporadic (or late-onset) Alzheimer’s. With genomic sequencing of the ADNI cohort,“I’m absolutely certain we will learn much more about how to diagnose and treat the disease,” Dr. Thies said. Like all of ADNI’s data, the genomic information will be publicly available to researchers all over the world. “More papers have been published outside of ADNI than by researchers in the group. That is really impressive. Sharing is clearly the road to progress.” How any new genetic information might be used is still an unknown, Dr. Thies said, but it’s likely to advance every aspect of Alzheimer’s care, from risk assessment to diagnosis to treatment. These kinds of data off er the possibility of being able to test people early in life and establish their risk of developing Alzheimer’s. “Having that information is going to very rapidly put us into the world of risk stratifi cation, so that we can optimally manage any interventions we develop.” Genetic information will also inform the search for preventive therapies, he said. “This will point us to new pathways in the disease process. Once those are identifi ed, we can try to fi nd early interventions that might help reduce the risk of getting Alzheimer’s.” Dr. Thies foreshadowed some expected results: “We are seeing risk genes beginning to clump around a number of areas, including those that have to do with amyloid, infl ammation, vascular areas, and lipid metabolism. ... These genes may end up showing just a modest eff ect on risk, but could still open the door to early intervention. If you can identify and treat someone for 20 years, a small but consistent eff ect may be enough to prevent Alzheimer’s from developing.” Dr. Robert Green of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, will lead ADNI. The project is funded by a number of bodies, including the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering, pharmaceutical companies, and nonprofi t groups. CfA