Experimental anti-amyloid treatment started before Alzheimer’s symptoms slowed memory loss

Summary: Solanezumab, an experimental anti-amyloid treatment, does not significantly slow the cognitive decline associated with Alzheimer’s disease.

Source: Brigham and Women’s Hospital

Preliminary results from a landmark clinical trial aimed at preventing symptoms of Alzheimer’s disease (AD) show that an investigational anti-amyloid drug, solanezumab, did not demonstrate a statistically significant slowing of cognitive decline associated with AD when initiated before the stage of clinical impairment.

The study of anti-amyloid therapy in asymptomatic Alzheimer’s disease (“A4 study”) was funded through a public-private partnership by the National Institute on Aging, part of the National Institutes of Health (NIH); Eli Lilly and company; Alzheimer Association; GHR Foundation; Foundation for the NIH; and several other organizations and donors.

The A4 study is coordinated by the Alzheimer’s Disease Therapeutic Research Institute at USC’s Keck School of Medicine and is an affiliate project of the Alzheimer’s Disease Clinical Trials Consortium. The A4 study was led by co-principal investigator Reisa Sperling, MD, director of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, a founding member of Mass General Brigham Health System.

“Unfortunately, our study results did not show evidence that solanezumab treatment slowed cognitive or functional decline in preclinical AD,” Sperling said. “We are very disappointed for our participants and their families, and for the hundreds of people who worked on this study for nearly a decade, but we will learn a lot from this work that will inform ongoing and future trials.”

No statistically significant difference was observed between the solanezumab and placebo groups on the primary endpoint, the Preclinical Alzheimer Cognitive Composite (PACC) (mean change (95% CI): placebo -1.4 (-1.76 , -1.04); solanezumab -1.69 (-2.13, -1.26); p-value=0.26). The secondary endpoint results were consistent with the primary endpoint, with all clinical outcomes numerically favoring placebo over solanezumab.

Longitudinal PET imaging of amyloid demonstrated that amyloid continued to accumulate over time in the placebo (65.9 centiloids baseline, 17.5 centiloids increase) and solanezumab (66.2 centiloids increase) groups. base centiloids, 12.1 augment centiloids). Higher baseline amyloid levels were strongly associated with an increased risk of progression to symptomatic Alzheimer’s disease (p-value<0.001).

Working closely with his co-principal investigator, Paul Aisen, MD, of the University of Southern California, Sperling and the A4 study team screened more than 6,800 participants, recruited from the Brigham and 66 other sites in the United States, Canada, Japan and Australia.

More than 1,150 eligible participants, ages 65 to 85, who had normal thinking and memory abilities but evidence of high amyloid plaque buildup, protein buildup in the brain, were randomized to the study treatment trial A4.

The researchers used an imaging test called a PET scan to determine if a potential participant had signs of amyloid plaque buildup, which begins years before the onset of AD symptoms and is thought to confer a high risk of cognitive decline. . Participants were randomized to receive a placebo or the experimental antibody, solanezumab, which binds to soluble forms of amyloid.

The study was double-blind, meaning neither the patients nor the researchers knew which people were receiving the treatment. Participants were studied for four and a half years in the double-blind phase with longitudinal cognitive tests, blood and imaging measures.

“We observed clear evidence that a greater amyloid burden at baseline was associated with a more rapid decline in the A4 study. More than a third of the participants progressed to a stage of clinical impairment during the study , driven by the group that started with the highest levels of amyloid,” Sperling said.

“Unfortunately, solanezumab did not have a substantial impact on amyloid plaque levels in the brain and did not slow cognitive decline.

“These results suggest that we probably need to be more aggressive with amyloid reduction, even at this very early stage of the disease, as we are testing in the AHEAD 3-45 study.”

In the AHEAD 3-45 study, Sperling and colleagues are testing lecanemab, a different anti-amyloid antibody, in a public-private partnership with NIH funding to Brigham and Eisai and Co. Lecanemab demonstrated amyloid reduction and positive clinical outcomes in late-stage symptomatic Alzheimer’s disease in the Clarity AD study. The AHEAD study is testing lecanemab in preclinical AD.

“The A4 study successfully demonstrated the feasibility of conducting a large-scale trial in people with signs of amyloid in their brains who are not yet showing symptoms, and we are very grateful to our very dedicated participants,” Sperling said.

“As we continue to analyze the data, we expect to learn much more about the factors that influence the rate of progression to dementia in Alzheimer’s disease.”

In a companion study to A4 called Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN), Sperling and his colleagues are also following a group of individuals who are not yet showing signs of amyloid buildup.

See also

This shows a diagram of the study

The A4 and LEARN studies incorporated additional innovative methods to track early decline, building on research conducted at Mass General Brigham as part of the Harvard Aging Brain Study demonstrating that clinically normal individuals with evidence of accumulation of amyloid plaque showed signs of subtle abnormalities in brain function and an increased risk. of cognitive decline, using sensitive pencil-and-paper tests.

This shows the outline of a brain
The primary endpoint of the A4 study was a set of tests that measure and track early signs of a decline in “normal” to subtly abnormal cognitive performance. Image is in public domain

The primary endpoint of the A4 study was a set of tests that measure and track early signs of a decline in “normal” to subtly abnormal cognitive performance. A4 was powered to detect a treatment effect of approximately 30 percent slowing of the rate of cognitive decline.

Other new measures were developed for the A4 study that are now being used in other Alzheimer’s disease prevention trials. Sperling and her colleagues, Dorene Rentz, PsyD, of BWH and MGH, and Kathryn Papp, PhD, of BWH, created a new name and face memory test to detect very early memory changes. Participants took these memory tests, using an iPad, every six months to study changes in computerized cognitive tests over time.

PET scans capable of detecting the other hallmark pathology of Alzheimer’s disease, tau tangles, known as Tau PET, were introduced in the A4 study, largely based on the work of Keith Johnson, MD, of MGH, in the Harvard Aging Brain Study.

Sperling says this approach builds on effective methods used with other chronic conditions.

“The approach we took for the A4 study is inspired by how we treat heart disease, diabetes and cancer,” she said. “We have made such advances in these diseases by identifying people who show signs of increased risk or silent disease detected by screening and initiating treatment before they show clinical symptoms of the disease.”

All screening data for the A4 and LEARN study has been widely shared with the Alzheimer’s field, and the full longitudinal dataset, including cognitive outcomes, images, and biological samples, will be shared. through the Alzheimer’s Disease Clinical Trials Consortium.

This information will be used to inform ongoing trials and design future studies to prevent symptoms of Alzheimer’s disease with other promising experimental agents.

About this Alzheimer’s disease and neuropharmacology research news

Author: Serena Bronda
Source: Brigham and Women’s Hospital
Contact: Serena Bronda – Brigham and Women’s Hospital
Picture: Image is in public domain

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