Cedernaes Jonathan, Schiöth Helgi B, Benedict Christian
Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Exp Gerontol. 2014 Sep;57:104-6. doi: 10.1016/j.exger.2014.05.002. Epub 2014 May 14.
A pharmaceutical intervention that has received great attention in recent years for treating Alzheimer's disease (AD) is the use of antibodies targeting amyloid beta (Aβ) in the brain, as the formation of Aβ plaques is considered as being the driving force for the development and progression of AD. Recently, a Phase III trial in patients with mild-to-moderate AD has provided ambivalent evidence for the efficacy of this intervention. In this trial, the intravenous administration of bapineuzumab, a monoclonal antibody targeting Aβ in the brain, for 78weeks led to a reduction of cerebrospinal fluid levels of phosphorylated tau and evidence for lower Aβ accumulation in the brain of AD patients who carried APOE ε4. However, this treatment did not improve clinical outcomes (e.g. the rate of cognitive decline) in these patients. Similar null results with respect to the rate of cognitive decline were found in a separate Phase III clinical trial after treatment with solanezumab. Based on these findings, one conclusion could be that antibodies targeting Aβ in the brain may unfold their highest efficacy when given before the development of clinical AD symptoms, i.e. during a period where neurodegeneration but not cognitive loss represents the major pathology. Another conclusion could be that antibody-based pharmaceutical interventions may fail to slow the progress of cognitive loss in patients who have AD because of their solely pharmaceutical therapeutic approach. Leisure activities that require patients' mental and physical abilities (e.g. exercise) are associated with a reduced risk of developing dementia. In the same manner, they may help to curb the progress of this devastating disease. Thus, combining the use of antibodies targeting Aβ with therapeutic strategies that require patients' mental and physical abilities might help tackle the neurodegenerative dynamics and cognitive loss both in patients with AD, and its prodromal state, mild cognitive impairment.
近年来，一种在治疗阿尔茨海默病（AD）方面备受关注的药物干预措施是使用针对大脑中β淀粉样蛋白（Aβ）的抗体，因为Aβ斑块的形成被认为是AD发生和发展的驱动力。最近，一项针对轻至中度AD患者的III期试验为这种干预措施的疗效提供了矛盾的证据。在该试验中，静脉注射bapineuzumab（一种针对大脑中Aβ的单克隆抗体）78周，导致携带APOE ε4的AD患者脑脊液中磷酸化tau水平降低，且大脑中Aβ积累减少。然而，这种治疗并未改善这些患者的临床结局（如认知衰退率）。在用solanezumab治疗后的另一项III期临床试验中，也发现了关于认知衰退率的类似阴性结果。基于这些发现，一个结论可能是，针对大脑中Aβ的抗体在临床AD症状出现之前给药，即在神经退行性变而非认知丧失是主要病理特征的时期给药，可能会发挥出最高疗效。另一个结论可能是，基于抗体的药物干预措施可能由于其单一的药物治疗方法而无法减缓AD患者认知丧失的进展。需要患者身心能力参与的休闲活动（如运动）与患痴呆症风险降低相关。同样，它们可能有助于遏制这种毁灭性疾病的进展。因此，将针对Aβ的抗体使用与需要患者身心能力的治疗策略相结合，可能有助于应对AD患者及其前驱状态轻度认知障碍患者的神经退行性变动态和认知丧失问题。
