Nat Rev Drug Discov

多个靶向β淀粉样多肽（Aβ）的AD药物在临床试验中被证明无效。即便如此，4个针对β淀粉样多肽的抗体药物显示能够介导清除AD病人大脑β淀粉样斑。最近，FDA通过使用淀粉样斑水平降低作为替代评价终点，加速审批通过了其中一个单抗药物，即阿杜卡单抗(aducanumab)。目前抗体药物被审批通过的合理性和其临床效果仍有巨大争议。本文提出了这个争议，从AD的两种病态蛋白聚合物的时间交互作用-β淀粉样斑和tau神经纤维缠结-以及它们之间的关系对认知功能损伤的角度，综述了针对靶向Aβ药物的临床试验数据，突出了能够影响临床疗效的药物特征的差异性。基于此，作者提出Aβ病理症状驱动了tao蛋白病理症状，β淀粉样斑需要被降低到一定水平（~20 centiloids）才能显示出显著的临床益处，并且Aβ的清除与临床效果之间有一定的延迟。作者总结，在临床实验中，大脑中淀粉样多肽被潜在治疗药物清除的速度是证明其临床获益的关键因素。

评语：

针对降低AD患者Aβ水平的大约20种药物在临床试验中均以失败告终，而aducanumab作为单抗药物降低了在AD脑内降低Aβ，FDA以此为评价终点加速审批通过它的使用，即使争议巨大，但对AD药物开发领域注入了信心。

Many drugs that target amyloid-β (Aβ) in Alzheimer disease (AD) have failed to demonstrate clinical efficacy. However, four anti-Aβ antibodies have been shown to mediate the removal of amyloid plaque from brains of patients with AD, and the FDA has recently granted accelerated approval to one of these, aducanumab, using reduction of amyloid plaque as a surrogate end point. The rationale for approval and the extent of the clinical benefit from these antibodies are under intense debate. With the aim of informing this debate, we review clinical trial data for drugs that target Aβ from the perspective of the temporal interplay between the two pathognomonic protein aggregates in AD - Aβ plaques and tau neurofibrillary tangles - and their relationship to cognitive impairment, highlighting differences in drug properties that could affect their clinical performance. On this basis, we propose that Aβ pathology drives tau pathology, that amyloid plaque would need to be reduced to a low level (~20 centiloids) to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe a clinical benefit. We conclude that the speed of amyloid removal from the brain by a potential therapy will be important in demonstrating clinical benefit in the context of a clinical trial.

Neurology

Objective: To identify the class of evidence for aducanumab use for the treatment of Alzheimer disease and present clinical considerations regarding use.

Methods: The author panel systematically reviewed available clinical trial data detailing aducanumab use in individuals with early symptomatic Alzheimer disease. Level of evidence statements were assigned in accordance with the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed.

Results: Data were identified from 4 clinical trials, 1 rated Class I and 3 rated Class II. The Class I study showed that single doses of aducanumab up to 30 mg/kg were safe and well tolerated. All 3 Class II studies provided evidence that aducanumab (3-10 mg/kg) decreased amyloid deposition on brain PET at 1-year vs placebo. Efficacy data in the Class II studies varied by dose and outcome, but aducanumab either had no effect on mean change on the Clinical Dementia Rating® Sum-of-Boxes scores or resulted in less worsening (vs placebo) that was of uncertain clinical importance. Adverse amyloid-related imaging abnormalities occurred in approximately 40% of individuals treated with aducanumab vs 10% receiving placebo.

Clinical context: Administration of aducanumab will require expanded clinical infrastructure. Evidence-based guidance is needed to address key questions (e.g., safety in populations not enrolled in Phase 3 studies, expected benefits on daily function, treatment duration) and critical issues relating to access to aducanumab (e.g., coverage, costs, burden of monthly infusions) that will inform shared decision-making between patients and providers.

Aging Cell

Inducing gamma oscillations with non-invasive light flicker has been reported to impact Alzheimer's disease-related pathology. However, it is unclear which signaling pathways are involved in reducing amyloid load. Here, we found that gamma frequency light flicker increased anchoring of amyloid precursor protein (APP) to the plasma membrane for non-amyloidogenic processing, and then physically interacted with KCC2, a neuron-specific K+ -Cl- cotransporter, suggesting that it is essential to maintain surface GABAA receptor α1 levels and reduce β-amyloid (Aβ) production. Stimulation with such light flicker limited KCC2 internalization and subsequent degradation via both tyrosine phosphorylation and ubiquitination, leading to an increase in surface-KCC2 levels. Specifically, PKC-dependent phosphorylation of APP on a serine residue was induced by gamma frequency light flicker, which was responsible for maintaining plasma membrane levels of full-length APP, leading to its reduced trafficking to endosomes and inhibiting the β-secretase cleavage pathway. The activated PKC from the gamma frequency light flicker subsequently phosphorylated serine of KCC2 and stabilized it onto the cell surface, which contributed to the upregulation of surface GABAA receptor α1 levels. Together, these data indicate that enhancement of APP trafficking to the plasma membrane via light flicker plays a critical modulatory role in reduction of Aβ load in Alzheimer's disease.