Amyloid beta (Aβ) plaque is a defining pathologic feature of Alzheimer disease (AD). Aducanumab, a monoclonal IgG1 that selectively binds aggregated species of Aβ, has been shown by amyloid positron emission tomography (Amyloid PET) to reduce Aβ plaques in patients with prodromal and mild AD. This is the first autopsy report of the AD neuropathology in a patient previously treated with aducanumab. The patient was an 84-year-old woman who was randomized to the placebo arm of the PRIME Phase 1b study (221AD103). The patient progressed to moderate dementia (MMSE = 14/30), beyond the targeted early AD treatment stage, before receiving aducanumab in the long-term extension (LTE). The patient then received 32 monthly doses of aducanumab, titrated up to 6 mg/kg, for a cumulative dose of 186 mg/kg. In the LTE, Amyloid PET scans demonstrated robust Aβ plaque reduction, from a composite standard uptake value ratio (SUVR) of 1.5 at screening to < 1.1 at 56 weeks post-aducanumab dosing. MRI examinations were negative for amyloid-related imaging abnormalities (ARIA). She passed away in hospice care 4 months after her last dose of aducanumab. The postmortem neuropathologic examination confirmed AD neuropathologic changes. Aβ and IBA1 immunohistochemistry assays demonstrated sparse residual Aβ plaque engaged by amoeboid reactive microglia. Phospho-Tau (pTau) immunohistochemistry demonstrated neocortical neurofibrillary degeneration (Braak stage V, NIA/AA Stage B3). However, the density of pTau neuropathology, including neuritic plaque pTau (NP-Tau), appeared lower in the PRIME LTE Patient compared to a reference cohort of untreated Braak stage V–VI, NIA/AA Stage B3 AD cases. Taken together, this case report is the first to provide Amyloid PET and neuropathologic evidence substantiating the impact of aducanumab to reduce Aβ plaque neuropathology in a patient with AD. Furthermore, this report underscores the critical importance of autopsy neuropathology studies to augment our understanding of aducanumab’s mechanism of action and impact on AD biomarkers.

淀粉样蛋白 (Aβ) 斑块是阿尔茨海默病 (AD) 的决定性病理特征。Aducanumab 是一种单克隆 IgG1，可选择性结合聚集的 Aβ，淀粉样蛋白正电子发射断层扫描 (Amyloid PET) 显示可减少前驱和轻度 AD 患者的 Aβ 斑块。这是先前接受过阿杜卡单抗治疗的患者的第一份 AD 神经病理学尸检报告。患者是一名 84 岁的女性，她被随机分配到 PRIME 1b 期研究 (221AD103) 的安慰剂组。在接受长期扩展 (LTE) 中的阿杜卡单抗之前，患者进展为中度痴呆 (MMSE = 14/30)，超过了目标早期 AD 治疗阶段。然后患者接受 32 个月的阿杜卡单抗剂量，滴定至 6 mg/kg，累积剂量为 186 mg/kg。在LTE中，淀粉样蛋白 PET 扫描显示 Aβ 斑块显着减少，从筛选时的复合标准摄取值比（ SUVR ）为 1.5 到阿杜卡单抗给药后 56 周时的 < 1.1。MRI 检查对淀粉样蛋白相关成像异常 (ARIA) 呈阴性。她在最后一次服用阿杜卡单抗后 4 个月在临终关怀中去世。尸检神经病理学检查证实了 AD 神经病理学变化。Aβ 和 IBA1 免疫组织化学测定表明变形虫反应性小胶质细胞参与的稀疏残留 Aβ 斑块。Phospho-Tau (pTau) 免疫组织化学显示新皮质神经原纤维变性（Braak V 期，NIA/AA B3 期）。然而，与未经治疗的 Braak V-VI 期参考队列相比，PRIME LTE 患者的 pTau 神经病理学密度，包括神经炎斑块 pTau (NP-Tau)，似乎较低，NIA/AA B3 AD 阶段案例。总而言之，本病例报告首次提供淀粉样蛋白 PET 和神经病理学证据，证实阿杜卡单抗对减少 AD 患者 Aβ 斑块神经病理学的影响。此外，该报告强调了尸检神经病理学研究对于增强我们对 aducanumab 的作用机制和对 AD 生物标志物的影响的理解的重要性。