WUSTL to lead new international Alzheimer’s disease research network

The Alzheimer’s Disease Research Center (ADRC) at Washington University School of Medicine in St. Louis will lead a six-year, $16 million international research collaboration dedicated to understanding inherited forms of Alzheimer’s disease. The National Institute on Aging (NIA) will fund the project.

Forms of Alzheimer’s disease linked to inherited mutations are rare but have provided scientists with many important insights into the more common “sporadic” forms of the disease. Because individuals with these inherited forms of Alzheimer’s are widely dispersed geographically, there have been too few at any one center to conduct extensive research. Through the newly created Dominantly Inherited Alzheimer’s Network (DIAN), investigators hope to organize and enroll a broad pool of qualified volunteers.

“For treatments now in development to be optimally beneficial for patients, we have to find ways of diagnosing Alzheimer’s disease as early as possible,” says DIAN principal investigator John C. Morris, M.D., the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and director of the ADRC. “That’s likely to happen much more quickly as we move from studying the few family members in St. Louis with inherited Alzheimer’s to the 300 family members who will be accessible through the DIAN.”

DIAN will include Washington University; a consortium involving Harvard University, Massachusetts General Hospital and Brown University; Columbia University; Indiana University; the University of California at Los Angeles; the University College of London’s Institute of Neurology at Queen’s Square; and a consortium of the universities of Brisbane, Perth and Sydney in Australia.

DIAN is modeled after the Adult-Children Study at the ADRC. That study regularly conducts detailed physical and mental assessments of healthy middle-aged children whose parents have been diagnosed with Alzheimer’s. Researchers hope this will help them to identify telltale changes in the central nervous system decades before the symptoms of Alzheimer’s disease become apparent.

“The Adult-Children Study is another genetic investigation, but it’s focused on less overtly inherited forms of the disease,” says Morris. “If a parent develops Alzheimer’s disease at a relatively young age in a family with no known mutation that causes the disease, a genetic factor that we have yet to identify may be present, and this can notably increase the risk to the children.”

Scientists are aware of inherited mutations in three genes that can cause Alzheimer’s disease: amyloid precursor protein, presenilin 1 and presenilin 2. Changes in all three genes cause Alzheimer’s to develop early, potentially pushing the age of onset down into a patient’s 50s, 40s or even 30s. Researchers believe all the mutations lead to increased production of amyloid beta 42, a protein fragment that is the principal ingredient of brain plaques found in Alzheimer’s patients. This has made amyloid beta a primary target for researchers developing new drugs for Alzheimer’ s disease.

Scientists already have several potential indicators, known as biomarkers, of the early onset of Alzheimer’s disease. However, the only current way to confirm their validity is to wait years or decades and see whether volunteers who have the biomarkers eventually get the disease. DIAN may help scientists shorten this process dramatically by allowing them to look for the potential biomarkers in individuals who have inherited a known mutation from an affected parent and are almost certain to develop the disease.

To get important clues about how and why the disease develops, scientists plan to closely monitor possible biomarkers in DIAN volunteers age 21 and older.

“The most exciting aspect of DIAN is that we have a chance to determine the type and order of brain changes that herald the onset of dementia in years to come,” says Morris. “If we’re going to develop preventive therapies, we have to know when to target each of the mechanisms in the brain that may be contributing to the beginnings of Alzheimer’s disease.”

If DIAN volunteers develop the disease, they will be monitored closely to assess how comparable the inherited and sporadic forms of Alzheimer’s are.

The grant includes travel funds to allow DIAN volunteers who enrolled at one network site to travel to another network site in order to participate in research unique to the other site.

The range of the seven sites raises a challenge for DIAN in ensuring that all research and diagnostic procedures are standardized so that data can be appropriately compared across all centers.

“If one institution obtains cerebrospinal fluid at 6 a.m. to test brain protein levels and another obtains samples at 6 p.m., it may be impossible to compare results because protein levels naturally fluctuate throughout the day,” Morris explains.

Morris has been a leader in the process of standardizing assessment procedures and practices. In 2005, he led the development of a comprehensive set of patient assessment procedures for the 29 federally funded Alzheimer’s disease research centers in the United States. He plans to work with other DIAN investigators to integrate these standards and others already developed for Alzheimer’s research into the new collaboration.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.