Noguchi-Shinohara Moeko, Shuta Kazuyoshi, Murakami Hidetomo, Mori Yukiko, Komatsu Junji, Kobayashi Chizuru, Hersch Steven, Horie Kanta, Ono Kenjiro
Department of Neurology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
Deep Human Biology Learning (DHBL), Eisai Co., Ltd, Tsukuba, Japan.
Ann Neurol. 2025 May;97(5):993-1006. doi: 10.1002/ana.27175. Epub 2025 Jan 6.
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.
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+).
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.
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.
Clarity AD III期试验表明，在早期阿尔茨海默病（AD）中，lecanemab可降低淀粉样蛋白标志物水平，且与安慰剂相比，认知和功能指标的下降程度更小。在此，我们旨在对lecanemab在不同AD阶段的活体参与者的脑脊液（CSF）中捕获的淀粉样β蛋白（Aβ）原纤维（PF）进行表征，以更好地理解体内lecanemab相关Aβ原纤维（Lec-PF）的动态变化。
我们新开发了一种独特且高度灵敏的免疫分析方法，使用lecanemab选择性捕获Lec-PF。在日本参与者（n = 163）中测量了Lec-PF、Aβ42、Aβ40、p-tau181、p-tau 217、总tau和神经颗粒素的脑脊液水平。本研究的参与者包括48名认知未受损的Aβ阴性（CU-）者、8名被诊断为疑似非阿尔茨海默病病理生理的认知受损者、9名认知未受损的Aβ阳性（CU+）者、34名轻度认知障碍的Aβ阳性（MCI+）者和64名患有AD痴呆的Aβ阳性（AD+）者。
与CU-组相比，MCI+组和AD+组的脑脊液Lec-PF水平显著升高。值得注意的是，在Aβ阳性参与者中，脑脊液Lec-PF与斑块相关生物标志物呈适度相关，与神经退行性变生物标志物（如脑脊液总tau和神经颗粒素）呈更强的相关性，这表明脑脊液Lec-PF水平在近端反映神经退行性变以及老年淀粉样斑块的数量。
这是首篇描述lecanemab在人脑脊液中捕获的Aβ-PF种类的报告，并支持Lec-PF与AD中的神经退行性变相关，且可能解释lecanemab临床疗效的机制。《神经病学纪事》2025年；97:993 - 1006。
