Study focuses on inherited Alzheimer’s up to 25 years before expected dementia onset

Washington University School of Medicine in St. Louis is launching an international clinical trial aimed at preventing Alzheimer's disease in people genetically destined to develop the illness at a young age. Unlike most other Alzheimer's prevention trials, this one will enroll people before the disease has taken hold – up to 25 years before the expected onset of dementia.

Called the Primary Prevention Trial, the new study will investigate whether gantenerumab — an investigational antibody under development for Alzheimer's disease by Roche and Genentech, a member of the Roche Group — can clear a key Alzheimer's protein called amyloid beta, and slow or stop the disease. Amyloid is the chief component of plaques that dot the brains of people with the disease. Many scientists suspect the disease originates from the buildup of amyloid plaques in the brain that start to develop up to two decades before symptoms of dementia begin.

Overwhelming evidence suggests that the most effective way to slow or stop amyloid beta is to prevent it from building up in the first place, but most of the drugs targeted to this protein have been tested in people who already have at least some early signs of the disease, such as memory loss – when the disease is far enough along that reducing amyloid alone isn't likely to stop it. We'll be recruiting participants as young as 18. In many ways, this trial will be a necessary test of the amyloid hypothesis, which has had a major influence on Alzheimer's research and drug development over the past 30 years."

Eric McDade, DO, Associate Professor of Neurology and the Trial's Principal Investigator, School of Medicine, Washington University

The new trial involves families with rare genetic mutations that cause Alzheimer's at a young age – typically in a person's 50s, 40s or even 30s. A parent with such a mutation has a 50% chance of passing the genetic mutation to a child, and any child who inherits the mutation is all but guaranteed to develop symptoms of dementia near the same age as his or her parent. This certainty gives researchers an opportunity to evaluate the effectiveness of drugs designed to prevent Alzheimer's.

Forestalling the earliest signs of disease could be game changing in the world of Alzheimer's prevention, and the study has garnered support from all quarters: a U.S. governmental agency, nonprofit organizations, individual benefactors, and the health-care company Roche and Genentech. More than $130 million has been earmarked for the trial, including grants totaling an estimated $97.4 million from the National Institute on Aging (NIA) of the National Institutes of Health (NIH), $14 million from the Alzheimer's Association and the GHR Foundation, and up to $11.5 million from longtime Washington University benefactor Joanne Knight of St. Louis and family, who have long supported Alzheimer's research at Washington University. In addition, the university has pledged to raise an additional $6.5 million. The trial is being conducted in close partnership with Roche and Genentech, which also is providing significant funding.

"We are thrilled to be part of this important clinical trial in one of the earliest stages of Alzheimer's studied to date," said Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech. "Our vision has always been to detect Alzheimer's early, before damage in the brain is irreversible, offering tools and treatment all along the journey for people at risk of the disease. Close collaboration between industry, academia and patients is so critical to achieve this and tackle the complex challenge of this disease."

The trial will recruit people with rare, early-onset forms of the disease, but the results also will further our understanding of Alzheimer's overall, which could benefit the millions of people living with the more common form, which affects people later in life. The processes that lead to memory loss and cognitive impairment in Alzheimer's are thought to be similar, whether the disease is caused by an inherited mutation or by the complex combination of genetics and environment that causes most Alzheimer's cases.

McDade and colleagues are studying about 230 participants from families that carry genetic mutations that lead to early-onset Alzheimer's disease. The participants come from sites on five continents and have no or very few amyloid deposits. The trial will test gantenerumab over four years, with a goal of determining whether early treatment will prevent the buildup of the toxic protein.

"This trial is the first of its kind in that it aims to intervene before the onset of significant neuropathology in those young adults who are at a very high risk of developing the debilitating symptoms of Alzheimer's dementia," said Laurie Ryan, PhD, chief of the Clinical Interventions and Diagnostics Branch in NIA's Division of Neuroscience. "We now know that changes in the brain can begin a decade or more before symptoms appear, so this trial is designed to provide another piece in the Alzheimer's prevention puzzle."

The new trial is the second international Alzheimer's prevention trial led by Washington University School of Medicine. The first trial, known as the Dominantly Inherited Alzheimer Network-Trials Unit-001 (DIAN-TU-001), began in 2012 and is ongoing. That trial was testing the effectiveness of drug treatments, including gantenerumab, in people who were likely to develop the disease during the trial because nearly all had some amyloid plaques at the time they entered it. Earlier this year, trial leaders reported from the DIAN-TU-001 study that, while the effects on clinical outcomes such as cognitive function were not clear, gantenerumab improved biomarkers of the disease. As a consequence, trial leaders have offered the drug to participants as part of an exploratory open-label extension and continue to monitor changes in measures of Alzheimer's disease in those participants who are receiving the investigational drug.

"Multiple drugs are being tested in the ongoing Knight Family DIAN-TU prevention trial, which involves people who are expected to develop symptoms within 10 years," said Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology and the principal investigator and program director of the Knight Family DIAN-TU. "Initiating a new prevention trial alongside the DIAN-TU-001 trial gives family members an opportunity to attempt to stop the disease even earlier – 10 years or more before symptoms are likely to arise, which is before or just as the first brain changes begin. It's the ultimate approach for prevention."

This new trial will draw from this same group of families and is aimed at determining whether targeting amyloid can prevent familial Alzheimer's disease. Success would give researchers additional reasons to continue pursuing amyloid-based therapies at the earliest stages of the disease.

"It's exciting to think of the valuable insights this groundbreaking trial will provide in the prevention of Alzheimer's dementia," said Fred Miller, GHR Foundation's chief operating officer and Alzheimer's program lead. "We're pleased to partner boldly on the multiple DIAN-TU trials, all made possible by the strong collaboration between academic researchers, government, industry, philanthropy and the DIAN families themselves."

Both trials are being conducted in association with the Dominantly Inherited Alzheimer Network (DIAN) – an NIH-funded international research network led by Washington University and involving nearly 40 research institutes in North America, Australia, Europe, Asia and South America. The National Institute on Aging has been a major supporter of DIAN and its clinical trials unit since the network was established in 2008.

"The Alzheimer's Association has been a long-term partner with DIAN, and we're particularly proud of providing the initial funding for the establishment and launch of the Trials Unit in March 2012," said Maria C. Carrillo, PhD, Alzheimer's Association chief science officer. "DIAN-TU is a landmark project and has dramatically accelerated the pace of discovery of treatment and prevention strategies for Alzheimer’s disease, and this innovative new prevention study is no exception."

This international effort to find ways to prevent Alzheimer's disease would not be possible without the support of many partners, as well as the active involvement of DIAN families.

"The stakes are high, and studies like this one are expensive to carry out," McDade said. "We're thankful for the support from many sources to make this trial possible. We're also grateful to the families, for their encouragement and willingness to take part in trials like this one."