  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.
