Lecanemab-Associated Amyloid-β Protofibril in Cerebrospinal Fluid Correlates with Biomarkers of Neurodegeneration in Alzheimer's Disease.

OBJECTIVE: The Clarity AD phase III trial showed that lecanemab reduced amyloid markers in early Alzheimer's disease (AD) and resulted in less decline on measures of cognition and function than placebo. Herein, we aimed to characterize amyloid-β (Aβ) protofibril (PF) captured by lecanemab in human cerebrospinal fluid (CSF) from living participants with different stages in AD, which enable an enhanced understanding of the dynamic changes of lecanemab-associated Aβ-PF (Lec-PF) in vivo. METHODS: We newly developed a unique and highly sensitive immunoassay method using lecanemab that selectively captures Lec-PF. The CSF level of Lec-PF, Aβ42, Aβ40, p-tau181, p-tau 217, total tau, and neurogranin were measured in Japanese participants (n = 163). The participants in this study consisted of 48 cognitively unimpaired Aβ-negative (CU-), 8 cognitively impaired diagnosed as suspected non-Alzheimer's disease pathophysiology, 9 cognitively unimpaired Aβ-positive (CU+), 34 Aβ-positive with mild cognitive impairment (MCI+), and 64 Aβ-positive with AD dementia (AD+). RESULTS: The CSF Lec-PF levels significantly increased in the groups of MCI+ and AD+ compared with CU- group. Notably, CSF Lec-PF showed modest correlation with plaque-associated biomarkers in Aβ-positive participants and stronger correlation with neurodegeneration biomarkers, such as CSF total tau and neurogranin, suggesting that CSF Lec-PF levels proximally reflect neurodegeneration as well as the amount of senile amyloid plaques. INTERPRETATION: This is the first report describing Aβ-PF species captured by lecanemab in human CSF and supporting that Lec-PF is correlated with neurodegeneration in AD and may explain the mechanism of the clinical effect of lecanemab. ANN NEUROL 2025;97:993-1006.