Teipel Stefan, Tang Yi, Khachaturian Ara
German Center of Neurodegenerative Diseases (DZNE), Rostock/Greifswald Rostock Germany.
Department of Psychosomatic Medicine University Medicine Rostock Rostock Germany.
Alzheimers Dement (N Y). 2025 Apr 9;11(2):e70083. doi: 10.1002/trc2.70083. eCollection 2025 Apr-Jun.
We aimed to determine the clinical efficacy of treating apolipoprotein E (ApoE) ε4 homozygotes with recently approved anti-amyloid antibodies.
Data were derived from supplementary analyses in the regulatory studies Clarity (lecanemab) and TRAILBLAZER-ALZ2 (donanemab). We used Bayesian reanalysis with an independent t-statistic to determine evidence for or against an effect of antibody treatment on Clinical Dementia Rating scale Sum of Boxes (CDR-SB) in ApoE ε4 homozygotes, and a Bayesian random-effect meta-analysis to determine the effect size.
The Bayesian reanalysis showed moderate evidence of no effect for both antibodies. For donanemab and lecanemab, the odds of no difference in treatment effect were nearly three times greater than the odds of a difference. The meta-analysis revealed a small effect of -0.06 CDR-SB points in favor of treatment with a moderate heterogeneity estimate. The Bayes factor was 0.26, indicating that the absence of an effect was almost four times more likely than the presence of an effect.
The most likely explanation for our results is the lack of a treatment effect for lecanemab and donanemab in ApoE 4 homozygotes. This could reflect inadequate exposure to the antibody due to more severe side effects, subsequent treatment interruptions, and lower dosing or a biologically driven lack of efficacy in a genetically determined disease. Our results support the view that excluding these cases from treatment is justifiable because of the higher risk of side effects and the lack of clinical efficacy.
Lecanemab and donanemab were clinically ineffective in ApoE ε4 homozygotes.ApoE ε4 homozygotes should not receive these treatments due to inefficacy.Future trials should adopt Bayesian analysis strategies.Bayesian analysis provides evidence for or against treatment effects.Bayesian inference provides clinically interpretable results.
我们旨在确定使用近期获批的抗淀粉样蛋白抗体治疗载脂蛋白E（ApoE）ε4纯合子的临床疗效。
数据来源于监管研究Clarity（lecanemab）和TRAILBLAZER - ALZ2（donanemab）的补充分析。我们使用独立t统计量的贝叶斯再分析来确定支持或反对抗体治疗对ApoE ε4纯合子临床痴呆评定量表方框总和（CDR - SB）有影响的证据，并使用贝叶斯随机效应荟萃分析来确定效应大小。
贝叶斯再分析显示两种抗体均无效应的证据适中。对于donanemab和lecanemab，治疗效果无差异的可能性几乎是有差异可能性的三倍。荟萃分析显示有一个小的效应，即有利于治疗的CDR - SB降低0.06分，异质性估计适中。贝叶斯因子为0.26，表明无效应的可能性几乎是有效应可能性的四倍。
我们结果最可能的解释是lecanemab和donanemab对ApoE 4纯合子缺乏治疗效果。这可能反映出由于更严重的副作用、随后的治疗中断、较低的给药剂量导致抗体暴露不足，或者在这种基因决定的疾病中存在生物学驱动的疗效缺乏。我们的结果支持这样一种观点，即由于副作用风险较高且缺乏临床疗效，将这些病例排除在治疗之外是合理的。
Lecanemab和donanemab对ApoE ε4纯合子临床无效。由于无效，ApoE ε4纯合子不应接受这些治疗。未来试验应采用贝叶斯分析策略。贝叶斯分析提供支持或反对治疗效果的证据。贝叶斯推断提供临床可解释的结果。
