Substantial Doubt Remains about the Efficacy of Anti-Amyloid Antibodies

Abstract

Alzheimer's disease (AD) is a prevalent, progressive, and ultimately fatal neurodegenerative disorder that is defined pathologically by the accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. There remains an unmet need for therapies that can halt or slow the course of AD. To address this need, the FDA has provided a mechanism, under its Accelerated Approval pathway, for potential therapeutics to be approved based in part on their ability to reduce brain amyloid. Through this pathway, two monoclonal anti-amyloid antibodies, aducanumab and lecanemab, have been approved for clinical use. More recently, another amyloid-lowering antibody, donanemab, generated a statistically significant outcome in a phase 3 clinical trial and will shortly come under FDA review. While these monoclonal antibodies are not yet routinely used in clinical practice, the series of recent positive clinical trials has fostered enthusiasm amongst some AD experts. Here, we discuss three key limitations regarding recent anti-amyloid clinical trials: (1) there is little to no evidence that amyloid reduction correlates with clinical outcome, (2) the reported efficacy of anti-amyloid therapies may be partly, or wholly, explained by functional unblinding, and (3) donanemab in its phase 3 trial had no effect on tau burden, the pathological hallmark more closely related to cognition. Taken together, these observations call into question the efficacy of anti-amyloid therapies.Comment: 11 pages, 2 figures; Update 11/18/2023: Added subheadings to manuscript to improve readability, added a new data point to Figure 1A and Figure 2 for the recently published A4 clinical tria