Data from unsuccessful Alzheimer’s trial may help future studies

The Anti-Amyloid Treatment in Asymptomatic AD (A4) trial released initial results in March 2023 that showed the research drug did not slow cognitive decline. However, the A4 study data may help researchers craft future Alzheimer’s prevention trials for better outcomes. 

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By Alzheimer's Prevention Bulletin
A decade ago, the landmark Anti-Amyloid Treatment in Asymptomatic AD (A4) Study began studying people who were cognitively healthy but had known amyloid deposits in their brains. The goal was to prevent the decline of memory and thinking skills with an anti-amyloid drug, solanezumab. Fast forward 10 years and the results are now being released.
“The results were very clear and consistent,” said co-principal investigator Reisa Sperling, MD, Director of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital in Boston. “We did not see any evidence that treatment with solanezumab slowed cognitive decline or the progression of Alzheimer’s disease. Solanezumab did slightly slow the rate of increase in amyloid in the brain but did not decrease amyloid plaque load.”
While the results are disappointing to the clinical and scientific community, and the hundreds of people who participated in the study, there is still much to learn from the A4 trial.
Dr. Sperling emphasizes that researchers need to be more aggressive about decreasing amyloid plaques in the brain even at the earliest stages of Alzheimer’s disease. The findings clearly show that the amount of amyloid in the brain is predictive of future decline. In other words, starting earlier when there is less amyloid in the brain and reducing amyloid plaque burden may be key factors.
The learnings from the A4 trial will help researchers design future Alzheimer’s studies. For example:
  • The data from A4 will be shared with researchers around the globe. Since A4 screening data was released several years ago, more than 1,000 scientists have downloaded the information to inform their prevention trials.
  • The cognitive function measurements used in A4 were very sensitive to changes in memory and thinking skills. These assessments can be used to track cognitive decline at very early stages of disease.
  • This summer, the team plans to present blood test and PET scan data that could help identify biomarkers that predict cognitive change.

A companion study associated with A4, LEARN, tracked participants who were not eligible for the A4 trial due to a lack of amyloid on screening PET scans. The people in LEARN did not show substantial cognitive decline over the 5 year period. “The LEARN data gives us hope if we can keep people at a lower level of amyloid from the very beginning, we might be able to prevent cognitive decline,” said Dr. Sperling.

The AHEAD study is a next generation trial based on the A4 study idea. With the FDA-approved drug lecanumab, the AHEAD study targets the earliest changes in the brain due to Alzheimer’s disease by enrolling participants as young as 55 years old with intermediate levels of amyloid. The study is expected to take about four years and is still enrolling participants

“The A4 results are really disappointing for us because we know how dedicated our participants were,” said Dr. Sperling who is also a co-principal investigator for the AHEAD study. “It was devastating to feel we did not help them. However, there is still much more A4 data to review which I hope will assist the field in developing future Alzheimer’s disease prevention studies."

For more information about participating in the AHEAD study or other research programs, please visit our Find a Study page.