Development of disease‐modifying treatments for Alzheimer's disease (AD) has been challenging, with no drugs approved to date. The failures of several amyloid‐targeted programs have led many to dismiss the amyloid beta (Aβ) hypothesis of AD. An antiamyloid antibody aducanumab recently showed modest but significant efficacy in a phase 3 trial, providing important validation of amyloid as a therapeutic target. However, the inconsistent results observed with aducanumab may be explained by the limited brain penetration and lack of selectivity for the soluble Aβ oligomers, which are implicated as upstream drivers of neurodegeneration by multiple studies. Development of agents that can effectively inhibit Aβ oligomer formation or block their toxicity is therefore warranted. An ideal drug would cross the blood‐brain barrier efficiently and achieve sustained brain levels that can continuously prevent oligomer formation or inhibit their toxicity. A late‐stage candidate with these attributes is ALZ‐801, an oral drug with a favorable safety profile and high brain penetration that can robustly inhibit Aβ oligomer formation. An upcoming phase 3 trial with ALZ‐801 in APOE4/4 homozygous patients with early AD will effectively test this amyloid oligomer hypothesis.

中文翻译：

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阿尔茨海默病治疗的前进之路：重新评估淀粉样蛋白级联假说

阿尔茨海默病 (AD) 疾病修饰疗法的开发一直具有挑战性，迄今为止还没有任何药物获得批准。几个针对淀粉样蛋白的计划的失败导致许多人驳回了 AD 的淀粉样蛋白 β (Aβ) 假说。抗淀粉样蛋白抗体 aducanumab 最近在 3 期试验中显示出中等但显着的疗效，为淀粉样蛋白作为治疗靶点提供了重要验证。然而，使用 aducanumab 观察到的不一致结果可能是由于脑渗透有限和对可溶性 Aβ 寡聚体缺乏选择性，多项研究将其作为神经退行性变的上游驱动因素。因此，开发能够有效抑制 Aβ 寡聚体形成或阻断其毒性的药物是有必要的。理想的药物将有效地穿过血脑屏障并达到持续的脑水平，从而持续阻止寡聚体形成或抑制其毒性。具有这些特性的后期候选药物是 ALZ-801，这是一种口服药物，具有良好的安全性和高脑渗透性，可以有力地抑制 Aβ 寡聚体的形成。即将在 APOE4/4 早期 AD 纯合子患者中使用 ALZ-801 进行的 3 期试验将有效地检验这种淀粉样蛋白寡聚体假设。