Genome Sequencing Set to Hunt for Alzheimer’s Clues

The largest-ever genome sequencing project is the newest weapon in the Alzheimer’s battle.

This new 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, Ph.D. “We are bound to discover new things.”

Improvements in both technology and cost make the project feasible for the first time. The genome sequencing will take about 16 weeks from start to finish, said Dr. Thies, chief medical and scientific officer of the Alzheimer’s Association. The project’s price tag is a modest $2 million ($1 million each from the Alzheimer’s Association and the nonprofit Brin Wojcicki Foundation).

The project is an offshoot of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Dr. Thies said in an interview. ADNI is a global effort to improve ways of identifying the best patients for clinical trials, using brain imaging and other biomarkers. The North American section of ADNI has a pool of 800 patients who have been followed since 2004.

“This will point us to new pathways in the disease process.”
The cohort “has been characterized to an extent that is almost unheard of in genetic studies,” Dr. Thies said.

Upon enrollment, subjects are stratified as having normal cognition, mild cognitive impairment, or Alzheimer’s disease. Close follow-up allows researchers to examine the natural history of Alzheimer’s progression and to identifying cognitive and physiological changes as they occur, as well as risk factors that predispose 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.

Genomic sequencing of the ADNI cohort adds a new reach to its capabilities.

“I’m absolutely certain we will learn much more about how to diagnose and treat the disease as we look at this new genomic information,” Dr. Thies said.

Like all of ADNI’s data, the genomic information will be publicly available to researchers all over the world. Public data sharing in research is a relatively new concept, and one that greatly increases the chances of success, he said. “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 offer 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 stratification, so that we can optimally manage any interventions we develop.”

Genetic information will also inform the search for preventive therapies, he added.

“This will point us to new pathways in the disease process. Once those are identified, we can try to find early interventions that might help reduce the risk of getting Alzheimer’s.”

Some early work on the genetics of disease pathways will be featured at the upcoming Alzheimer’s Association International Conference in Vancouver, B.C.

“We are seeing risk genes beginning to clump around a number of areas, including those that have to do with amyloid, inflammation, vascular areas, and lipid metabolism,” Dr. Thies said. “These genes may end up showing just a modest effect 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 effect 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 the project.

ADNI 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 nonprofit groups.

 

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