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Researchers from Washington University School of Medicine in St. Louis are taking part in a multisite study to investigate the biomarkers of Alzheimer’s disease in people with Down syndrome. By middle age, nearly all people with Down syndrome show signs of Alzheimer’s disease, and doctors have no way to prevent it or to stop the disease from worsening.
A better understanding of how Alzheimer’s develops in this population could open up new possibilities for Alzheimer’s therapies for the hundreds of thousands of people living with Down syndrome in the U.S. — and maybe even lead to insight that could benefit the millions of other people with Alzheimer’s.
Led by the University of Pittsburgh, the project is supported by a grant expected to total $109 million over five years from the National Institutes of Health (NIH).
The award is part of NIH’s INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) project, which seeks to investigate conditions that affect individuals with Down syndrome and the general population, such as Alzheimer’s disease, autism, cataracts, celiac disease, congenital heart disease and diabetes. NIH’s National Institute on Aging and the Eunice Kennedy Shriver National Institute of Child Health and Human Development also are funding this project.
“Adults with Down syndrome are at high risk for developing Alzheimer’s disease because of their unique biology, usually starting in their late 40s, and the vast majority of individuals with Down syndrome will eventually develop the disease by their late 60s,” said principal investigator Benjamin Handen, PhD, professor of psychiatry at Pitt. “It’s a significant problem for that population, but we think that whatever we can learn from the biomarkers in people with Down syndrome can not only help them, but also the general population in terms of how we can intervene. We’re hoping this research will guide us toward prevention and treatment trials.”
Beau M. Ances, MD, PhD, the Daniel J. Brennan, MD, Professor of Neurology and a professor of radiology and of biomedical engineering at Washington University, is the study’s site director at the School of Medicine. He leads a project to map the molecular changes that occur in the brain as Alzheimer’s develops in people with Down syndrome. In the general population, Alzheimer’s develops in a clear sequence over the course of two decades or more before symptoms arise. First, plaques of amyloid proteins form in the brain, then tangles of tau protein. Some brain areas begin to shrink, communication networks between distant parts of the brain start to decay, and symptoms such as memory loss and confusion appear.
“The project I’m leading is an attempt to place individuals with Down syndrome within this Alzheimer’s framework,” Ances said. “When does amyloid start building up? How long after we see the first signs of tau do the patients show significant changes in their cognition? We think that Alzheimer’s disease in people with Down syndrome is likely to follow a similar trajectory as Alzheimer’s in the general population, but we don’t know that for sure. After all, the roots of the disease are different.
“In people with Down syndrome, Alzheimer’s is a genetic disease. It is caused by the same chromosomal duplication that gave them Down syndrome. In the general population, there are a lot of risk factors at play, some genetic, some not. So we need to know what, if anything, is different about Alzheimer’s in these two populations.”
People with Down syndrome have an extra copy of chromosome 21. Since the gene for amyloid is located on chromosome 21, the extra copy of the gene drives people with Down syndrome to produce too much amyloid, which builds up in their brains and sparks the destructive sequence of molecular events that culminates in Alzheimer’s disease. But chromosome 21 also carries many other genes, and some of those genes may also influence when and how Alzheimer’s arises.
Carlos Cruchaga, PhD, a professor of psychiatry, of genetics and of neurology at Washington University, leads a project to investigate whether any of the other genes on chromosome 21 contribute to the development of Alzheimer’s in people with Down syndrome.
The long-term goal is to lay the groundwork for a clinical trial to assess whether drugs that target amyloid can prevent or treat Alzheimer’s disease in people with Down syndrome. Several such experimental drugs are ready for testing in people.
“We have the best chance of stopping Alzheimer’s disease if we treat it before symptoms arise,” Ances said. “In people with Down syndrome, we have a group of people who we know have too much amyloid, and we know they are going to develop Alzheimer’s if we do nothing. So they are the perfect candidates for anti-amyloid therapeutics. If any of these drugs succeed in lowering amyloid in their brains, it may, hopefully, protect them from developing this terrible disease.”
In the meantime, Ances has partnered with John N. Constantino, MD, the Blanche F. Ittleson Professor of Psychiatry and Pediatrics, and co-director of the Intellectual and Developmental Disabilities Research Center at Washington University, to launch a clinic to provide care for people with Down syndrome who also have Alzheimer’s disease. The clinic is not funded by this grant, but it provides clinical care that complements research funded by the grant.
“What’s unique about St. Louis is that we have both a strong Down syndrome community and a strong Alzheimer’s research community,” Ances said. “In the past, people with Down syndrome often didn’t survive into middle age, and there isn’t a lot of awareness that Alzheimer’s disease almost always arises and becomes a problem for people with Down syndrome as they age. The necessary neurological and psychiatric support hasn’t always been available to them. So we established this clinic to provide neurologic and psychiatric care tailored to the needs of this population.”
As part of the grant, the research teams will assess and examine a wide range of data, from plasma-based biomarkers to biofluids, genetic factors, neuroimaging and everyday cognitive and psychological function. Research participants will be seen every 16 months for up to four visits.
Researchers at University of Wisconsin-Madison; University of Cambridge; Columbia University; New York State Institute for Basic Research in Developmental Disabilities; University of California, Irvine; University of Kentucky; Massachusetts General Hospital; University of North Texas Health Science Center; the University of Southern California’s Mark and Mary Stevens Neuroimaging and Informatics Institute, and Alzheimer’s Therapeutic Research Institute; and Johns Hopkins University also are part of this initiative.
For more information about the study, visit: https://www.nia.nih.gov/health/abc-ds-information-patients-and-families.
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