Preprint Open Access

The anti-amyloid monoclonal antibody Lecanemab: 16 cautionary notes

Kepp, Kasper P.; Sensi, Stefano L.; Johnsen, Kasper B.; Barrio, Jorge R.; Høilund-Carlsen, Poul F.; Neve, Rachael L.; Alavi, Abass; Herrup, Karl; Perry, George; Robakis, Nikolaos K.; Vissel, Bryce; Espay, Alberto J.

The recent CLARITY AD results for the monoclonal anti-amyloid antibody Lecanemab have been interpreted as promising, supporting the amyloid hypothesis of Alzheimer’s disease and leading to consideration for approval by the Food and Drug Administration. Here we explain why the claimed benefits on cognition and activities of daily living are uncertain, why Lecanemab may yield net harm for some subsets of patients and why the data do not prove the amyloid hypothesis but support other important population covariates driving disease. We note potential biases in the cohort arising from inclusion bias, unblinding, and dropouts, among other issues, which may affect the veracity of the data. Together with substantial adverse effects and subgroup heterogeneity, we conclude that Lecanemab’s efficacy is not clinically meaningful and may be insignificant when considering the study limitations and biases highlighted. The data are consistent with numerous analyses to date suggesting that Aβ and its derivatives are not the main causative agents of Alzheimer’s dementia.

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