Results were presented on Monday from the first-of-its kind Anti-Amyloid treatment in Asymptomatic Alzheimer’s (A4) Study. The A4 was a more than 10-year project to conduct one of the first and largest “preclinical” Alzheimer’s disease clinical trials, testing a compound for potential disease-slowing properties before memory problems begin in a population deemed at risk based on an amyloid PET scan biomarker test. Unfortunately, the drug studied, solanezumab, did not slow memory worsening compared to placebo in this trial. This was surprising given the previous findings in which solanezumab had appeared to have very small but seemingly real effects in symptomatic populations. In contrast, it had no benefit in A4 and seemed to make cognitive performance worse in patients who received it. This suggests that we need to better understand the role of different amyloid species at different stages of disease; solanezumab is specific for soluble forms of amyloid and does not lower brain amyloid plaques the way the recently approved anti-amyloid therapies do.
The A4 Study, however, was highly successful in demonstrating that preclinical AD trials could be done, and that they are needed. In A4, how much amyloid a person had in their brain had a major impact on the amount of memory decline they experienced in the 4.5 years of the study. The more amyloid a person had, the more memory loss they experienced. This suggests that targeting early stages, when amyloid is lowest, is the best time to initiate disease-slowing therapies and that we should try to lower amyloid as much as possible. In fact, in the slides you can see on the A4 website (https://a4study.org/study-results/) you’ll notice that there are essentially four groups in the A4 analyses: those with high, moderate, low amyloid (the green, blue, and purple lines on slide 6), and those with no amyloid (the yellow line on slide 7). The last group is from the LEARN Study, a group of people who didn’t qualify for A4 but were followed off drug as a comparator. The amount of memory loss experienced was greatest in the high amyloid group, lower in the lower amyloid groups, but lowest in the no amyloid group. On going trials aim to test whether lowering brain amyloid levels can “move” people from the purple and blue lines to the green and yellow lines and to where many people in the field believe we will have the greatest success and impact in the fight against Alzheimer’s disease.