A4 study data now available to aid preclinical Alzheimer’s research
Study is largest trial of pre-symptomatic Alzheimer’s disease patients
Data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study, the first and largest to focus on people who have early signs of Alzheimer’s disease but are not yet showing symptoms, are now available to researchers around the world.
Recognizing a need for starting treatment before any symptoms appear, the A4 study (NCT02008357) covered 1,169 people, ages 65 to 85, who had imaging evidence of amyloid plaques, toxic deposits of amyloid protein in the brain that are a hallmark of Alzheimer’s.
Over as long as eight years, a team led by researchers at the Keck School of Medicine of the University of Southern California collected brain scans, blood samples, genetic data, and cognitive tests from each person in the study. All data were de-identified to prevent personal identities from being revealed.
The dataset has already provided key insights into Alzheimer’s, and sharing the A4 study data widely is expected to drive further understanding of how Alzheimer’s develops and progresses.
“We were able to track decline and gain a much deeper understanding of this stage of the disease,” Paul Aisen, MD, co-leader of the A4 study, said in a USC press release. “Now, we want to make sure everybody has access to this information.”
Brain changes start before symptoms appear
Aisen, a professor of neurology and founding director of the Keck School of Medicine’s Alzheimer’s Therapeutic Research Institute (ATRI), said it is “essential to share all that we’ve learned with anyone else who can study this.”
Alzheimer’s begins with memory lapses, such as forgetting recent conversations or place names. As the disease progresses, memory loss becomes more severe, and additional symptoms, such as confusion and difficulty planning, can develop.
While Alzheimer’s is usually diagnosed in its early stage, the brain alterations that occur over the course of disease can begin many years before any symptoms manifest. This preclinical stage, with a buildup of amyloid plaques but no cognitive decline, is seen as an ideal time to slow Alzheimer’s progression.
The goal of the A4 study was to carry out Phase 3 testing of solanezumab against a placebo in older people at risk for memory loss. It was sponsored by Eli Lilly, which developed solanezumab, an experimental antibody designed to clear amyloid from bodily fluids to prevent it from depositing into plaques.
While solanezumab failed to reduce amyloid compared with the placebo, or slow Alzheimer’s over 4.5 years, the team found that the gradual buildup of amyloid in the brain was strongly linked to memory loss and cognitive decline.
The team also developed a test that can predict elevated amyloid in the brain by measuring the levels of certain amyloid fragments in the blood, which can help monitor amyloid buildup early in the course of Alzheimer’s.
The A4 study’s dataset may support research in preclinical Alzheimer’s, including the ongoing AHEAD3-45 study (NCT04468659), which is testing Leqembi (lecanemab), an antibody-based treatment approved in the U.S. last year for early Alzheimer’s with mild cognitive impairment or mild dementia.
“This dataset is part of a much larger and longer-term commitment to open science,” said Gustavo Jimenez-Maggiora, ATRI’s director of informatics. “Sharing it with the broader scientific community,” Jimenez-Maggiora said, could “support and accelerate further discoveries in Alzheimer’s disease research.”
In addition to A4, the LEARN study (NCT02488720) — Longitudinal Evaluation of Amyloid Risk and Neurodegeneration — monitored cognitive decline in more than 500 adults, ages 65 to 85, who did not have enough amyloid to be eligible for the A4 trial, offering a point of comparison for future research in preclinical Alzheimer’s.
The Global Research and Imaging Platform, a nonprofit, made possible the platform for sharing the A4 study data.
“We are breaking new ground here, but we’re also continuing to work on our platform — including developing new approaches to data visualization and data exploration — to make it as useful as possible to investigators at all stages of training and professional experience,” Aisen said.
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