– A new Alzheimer’s disease prevention study has randomly assigned its first participant to a treatment group — a critical step known as randomization — helping researchers see if Alzheimer’s can be prevented in a population at the highest risk for developing the disease. Researchers from Banner Alzheimer’s Institute are collaborating with investigators in Colombia to test for the first time whether certain medications, either alone or in combination, can prevent the disease among people who are predestined to develop Alzheimer’s at an early age.
The novel study is recruiting participants from the Colombian autosomal dominant Alzheimer’s disease (ADAD) kindred, the world’s largest group of individuals who have a mutation of the presenilin 1 (PSEN1) gene that makes the estimated 1,200 carriers nearly certain to develop Alzheimer’s disease at an average age of 44.
In the first part of the study, cognitively unimpaired and mildly impaired ADAD gene carriers will receive an antibody therapy that has been shown to remove amyloid plaques and slow cognitive decline in older Alzheimer’s patients. In the second part of the study, less frequent doses of this antibody therapy, an orally administered drug designed to reduce the production of amyloid, and a combination of these treatments will be compared in terms of their ability to stave off the return of plaques and other biological measurements of the disease.
“The random assignment of our first participant to a treatment group marks an important milestone in this trial advancing efforts to prevent and hopefully end Alzheimer’s disease,” said the corresponding principal investigator Robert Alexander, MD, chief scientific officer of the Alzheimer’s Prevention Initiative (API), an international collaborative formed in 2009 and led by Banner Alzheimer’s Institute in Phoenix. “We are very grateful to the members of these families whose participation is making this research possible and generating valuable information that could help every person facing Alzheimer’s.”
The trial led by Banner Alzheimer’s Institute and the Neurosciences Group at the University of Antioquia (GNA) in Medellín, Colombia, first aims to remove plaque as completely as possible from the brains of 200 cognitively impaired and unimpaired PSEN1 gene mutation carriers using donanemab, Eli Lilly and Company’s FDA-approved antibody therapy.
In the second part of the trial, participants will be randomly assigned to one of four groups. One group will continue to receive donanemab infusions. Another will receive Roche’s nivagacetor, an investigational oral gamma secretase modulator designed to limit production of amyloid protein. These two therapies aim to reduce plaque buildup via different approaches. The third group will receive both therapies to determine whether the combination of different mechanisms works better than either alone. Finally, the fourth group will receive placebo versions of both therapies. Those receiving only a single active therapy will receive a placebo version of the other. The trial also is recruiting 40 people without the genetic mutation to receive a placebo as a control group.
The new ADAD prevention trial builds on the history, partnership, infrastructure and learnings of the first API ADAD Colombia Trial, which launched a new era in Alzheimer’s prevention research when it was announced by the National Institutes of Health in 2012. That trial of the investigational antibody crenezumab was also conducted with members of the Colombian PSEN1 kindred, which includes roughly 6,000 distant relatives identified by GNA, some 1,200 of whom carry the ADAD-causing E280A genetic mutation. Though crenezumab failed to clear plaques, the trial laid the foundation for ongoing efforts to conduct further prevention research.
“With the Antioquia families’ help, we will determine the extent to which the antibody treatment clears amyloid plaques in the unimpaired and impaired stages of ADAD and how effective the different approaches are at maintaining low amyloid levels following plaque removal,” said David Aguillón, MD, GNA’s director and principal investigator of the University of Antioquia study site. “We remain committed to finding effective Alzheimer’s prevention therapies that will not only help the families in Antioquia, but others across the world.”
The new study is supported by an approximately $74.5 million grant from the National Institute on Aging, the lead U.S. federal agency supporting and conducting research into Alzheimer’s and related dementias. Lilly and Roche are generously donating the drug supplies that will be evaluated in this study. The study is led by Drs. Alexander and Jessica Langbaum from Banner Alzheimer’s and the API, Dr. Aguillón from the University of Antioquia, and Dr. Yakeel Quiroz from Massachusetts General Hospital.
In addition to providing new information about treatments to reverse and subsequently prevent the return of certain biological disease changes, the study will provide a shared resource of data and blood samples for researchers in the field to advance the scientific fight against Alzheimer’s.
API also received a $3 million grant from the Zurich-based NOMIS Foundation to continue to assess about 2,000 mutation carriers and non-carriers from the PSEN1 E280A kindred, provide a shared resource of longitudinal data and blood samples for the field, accelerate enrollment in the new prevention trial, and provide education and social support for the families irrespective of their participation in the study.
