Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
Department of Pharmacology (adjunct), University of Pennsylvania, Philadelphia, Pennsylvania, USA.
ASN Neuro. 2020 Jan-Dec;12:1759091420918557. doi: 10.1177/1759091420918557.
Late-onset Alzheimer’s disease (LOAD) is a long-enduring neurodegenerative disease that progresses for decades before the symptoms of cognitive decline and loss of executive function are measurable. Amyloid deposits among other pathological changes, tau hyperphosphorylation, synapse loss, microglia and astroglia activation, and hippocampal atrophy are among the pathological hallmarks of the disease. These are present in the brain before memory complaints are reported and an AD diagnosis is made. The attempt to postpone or prevent the disease is becoming a more and more plausible goal because new early electrophysiological, cognitive, blood-based, and imaging-based diagnostics are being brought forward at the same time as the first anti-amyloid antibody is about to be approved. In view of known contributions of neuroinflammation to the pathology of LOAD, we should not focus solely on anti-amyloid therapies and ignore the interactive neuroinflammatory component of AD. Our belief is that it would be more rewarding to start clinical trials using combination therapies that are based on approved, safe, and efficacious anti-neuroinflammatory agents such as anti-interleukin-1 signaling agents in combination with the anti-amyloid antibodies that have been shown to be safe in multiyear trials. The proposal is that we should administer these two classes of safe biologicals to symptom-free individuals in midlife who are identified as having a high-risk-for-Alzheimer’s-disease using “precision medicine.”
迟发性阿尔茨海默病（LOAD）是一种长期存在的神经退行性疾病，在认知能力下降和执行功能丧失的症状可测量之前，它会持续数十年发展。淀粉样蛋白沉积等病理学变化、tau 过度磷酸化、突触丧失、小胶质细胞和星形胶质细胞激活以及海马体萎缩是该疾病的病理学特征之一。这些在出现记忆问题和 AD 诊断之前就已经存在于大脑中。由于新的早期电生理学、认知、基于血液和基于成像的诊断方法同时出现，同时第一种抗淀粉样蛋白抗体即将获得批准，因此推迟或预防该疾病的尝试变得越来越合理。鉴于神经炎症对 LOAD 病理学的已知贡献，我们不应仅专注于抗淀粉样蛋白疗法，而忽略 AD 的相互作用神经炎症成分。我们认为，使用基于已批准的、安全且有效的抗神经炎症药物的联合疗法进行临床试验会更有成效，例如抗白细胞介素-1 信号通路的药物与在多年试验中已证明安全的抗淀粉样蛋白抗体联合使用。这一建议是，我们应该使用这两类安全的生物制剂对无症状的中年人进行治疗，这些中年人通过“精准医学”被确定为具有患 AD 的高风险。
