The recently published results of the 18-month randomized controlled trial of lecanemab, reporting the efficacy of the drug in slowing the progression of early Alzheimer’s disease, quickly led to approval by the FDA and widespread acceptance of lecanemab treatment. However, there are a number of matters that deserve further consideration. The success of blinding was not assessed, even as infusion reactions and the cerebral pathology underlying amyloid related imaging abnormalities could have signaled to many participants that they were on drug, potentially exerting a potent placebo effect. The value of the outcome to participants is not defined in the absolute terms necessary for clinical decision making and the difference attributable to lecanemab was between 18% and 46% of estimates of the minimal clinically important difference on the Clinical Dementia Rating Scale Sum of Boxes. The attenuation of change on the Alzheimer’s Disease Assessment Scale-Cognitive14 achieved by lecanemab at 18 months was 50% of that achieved by donepezil at six months. Lecanemab treatment imposes a high treatment burden. The fact that the burden commences at the initiation of lecanemab treatment whereas the benefit accrues years later requires us to take into account value discounting over time, which would significantly reduce the benefit/burden ratio. Finally, treatment with monoclonal antibodies to cerebral amyloid has consistently been associated with progressive cerebral atrophy. At the least, these issues should be raised in treatment discussions with patients. They also suggest a need to very seriously reconsider how we evaluate clinical trial results preparatory to translating them into clinical practice. Some suggestions are provided.

Stephen Nadeau is a graduate of MIT and the University of Florida College of Medicine. He has published broadly in the fields of cognitive and behavioral neurology, cognitive neuroscience, computational neuroscience, neurorehabilitation, and the opioid crises. He has conducted many small randomized controlled trials and been on the leadership teams of two Phase III trials. His clinical practice has centered on patients with cognitive impairment of many etiologies, including Alzheimer’s disease.