Alzheimer Prevention Trial Receives $74.5 Million NIH Grant

A $74.5 million five-year grant from the National Institute on Aging, part of the National Institutes of Health (NIH), will explore Alzheimer disease prevention. The two-part study will be conducted in members of the world's largest autosomal dominant Alzheimer disease (ADAD) kindred in Colombia who carry a genetic mutation that makes them all but destined to develop Alzheimer and become cognitively impaired at an average age of 44.

The study is led by Banner Alzheimer's Institute in Phoenix and the Neurosciences Group at the University of Antioquia (GNA) in Medellin, Colombia. It will initially aim to remove amyloid plaques as completely as possible in cognitively impaired and unimpaired carriers of the presenilin 1 (PSEN1) E280A mutation, and then evaluate different ways to stave off the recurrence of plaque deposits and other ensuing elements of the disease. Enrollment is expected to begin in the fall of 2025.

The first part of the study will use Eli Lilly and Company's (Lilly) antibody therapy donanemab to remove existing plaques as completely as possible (i.e., to levels consistent with a negative amyloid PET scan). Donanemab has been shown to clear amyloid plaques and slow cognitive decline, and was recently approved by the FDA for use in patients with mild cognitive impairment and dementia due to Alzheimer. The study will provide new information about the drug's safety, tolerability, and biological efficacy in the unimpaired and impaired stages of ADAD.

The second part of the study will compare the following approaches in the same participants, for safety, tolerability and ability to avert amyloid plaque accumulation and other biological and clinical features of the disease:

• Mutation carriers who will continue to receive donanemab infusions, as in the study's first part
• Those who will receive RG6289, Roche's investigational gamma secretase modulator, an orally administered drug intended to limit the production of amyloid protein that is prone to aggregate in Alzheimer disease
• Those who will receive a combination of these two drug treatments
• Those who will be followed on placebo

This study builds on the history, partnership, infrastructure and learnings of the original API ADAD Colombia Trial, which launched a new era in Alzheimer prevention research when it was announced by NIH in 2012.

While the investigational drug in the original trial with crenezumab failed to clear plaques or demonstrate a clinical benefit, the study introduced paradigms to speed up the evaluation of promising prevention therapies, found ways to do so in a vulnerable population in a developing country, and led to a growing number of prevention trials, some of which may find the first effective Alzheimer prevention therapies within the next few years. Both the original and the new trial tap into GNA's identification of about 6,000 distant relatives from the Colombian PSEN1 E280A kindred, including about 1,200 who carry the ADAD-causing genetic mutation.

"We are excited about the chance to advance the fight against Alzheimer disease in partnership with our outstanding colleagues and these unique families in Colombia," said Robert Alexander, MD, the API's chief scientific officer and one of the prevention trial leaders. "This study will clarify the extent to which the antibody treatment reduces amyloid plaques in the unimpaired and impaired stages of ADAD and test different approaches to maintain low amyloid levels following plaque removal."

The new study will enroll 200 cognitively unimpaired and mildly impaired mutation carriers and 40 non-carriers (who will receive placebo) from the Colombian kindred.

"This trial is a testament to our dear friend and longstanding partner, Dr Francisco Lopera, who established GNA, forged a close working relationship with API, and could not have been more committed to these families," said Eric M. Reiman, MD, executive director of Banner Alzheimer's Institute and one of the other API leaders. "He constantly said, 'My families are waiting,' and he played indispensable roles in the effort to find effective prevention therapies."

"I am honored to follow in Dr Lopera's footsteps and continue our work with API," said David Aguillón, MD, GNA's new director and principal investigator of the University of Antioquia study site. "Dr Lopera and the Antioquia families have inspired all of us to never give up, to maintain our sense of urgency to find effective Alzheimer prevention therapies, and to do so in ways that will help our Antioquia families."