Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Alzheimers Dement. 2022 Dec;18(12):2687-2698. doi: 10.1002/alz.12624. Epub 2022 Feb 24.
The amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly challenged. Here, we aim to refocus the amyloid cascade hypothesis on its original premise that the accumulation of amyloid beta (Aβ) peptide is the primary and earliest event in AD pathogenesis as based on current evidence, initiating several pathological events and ultimately leading to AD dementia.
An ongoing debate about the validity of the amyloid cascade hypothesis for AD has been triggered by clinical trials with investigational disease-modifying drugs targeting Aβ that have not demonstrated consistent clinically meaningful benefits.
It is an open question if monotherapy targeting Aβ pathology could be markedly beneficial at a stage when the brain has been irreversibly damaged by a cascade of pathological changes. Interventions in cognitively unimpaired individuals at risk for dementia, during amyloid-only and pre-amyloid stages, are more appropriate for proving or refuting the amyloid hypothesis. Our updated hypothesis states that anti-Aβ investigational therapies are likely to be most efficacious when initiated in the preclinical (asymptomatic) stages of AD and specifically when the disease is driven primarily by amyloid pathology. Given the young age at symptom onset and the deterministic nature of the mutations, autosomal dominant AD (ADAD) mutation carriers represent the ideal population to evaluate the efficacy of putative disease-modifying Aβ therapies.
Key challenges of the amyloid hypothesis include the recognition that disrupted Aβ homeostasis alone is insufficient to produce the AD pathophysiologic process, poor correlation of Aβ with cognitive impairment, and inconclusive data regarding clinical efficacy of therapies targeting Aβ. Challenges of conducting ADAD research include the rarity of the disease and uncertainty of the generalizability of ADAD findings for the far more common "sporadic" late-onset AD.
The amyloid cascade hypothesis, modified here to pertain to the preclinical stage of AD, still needs to be integrated with the development and effects of tauopathy and other co-pathologies, including neuroinflammation, vascular insults, synucleinopathy, and many others.
阿尔茨海默病（AD）的淀粉样蛋白级联假说受到越来越多的质疑。在这里，我们根据当前的证据，旨在重新关注淀粉样蛋白级联假说的原始前提，即β淀粉样蛋白（Aβ）肽的积累是 AD 发病机制中的首要和最早事件，引发了几个病理事件，并最终导致 AD 痴呆。
针对 Aβ 的靶向治疗 AD 的疾病修饰药物的临床试验未能显示出一致的、具有临床意义的益处，这引发了关于淀粉样蛋白级联假说有效性的持续争论。
针对 Aβ 病理学的单一疗法在大脑已经被一系列病理变化不可逆地损害的阶段是否能显著获益，这是一个悬而未决的问题。在出现痴呆风险的认知正常个体中，在仅出现淀粉样蛋白和淀粉样前阶段时进行干预，更适合证明或反驳淀粉样蛋白假说。我们的更新假说指出，当 AD 的临床前（无症状）阶段开始时，抗 Aβ 研究性治疗可能最有效，特别是当疾病主要由淀粉样蛋白病理学驱动时。鉴于发病年龄较早和突变的确定性，常染色体显性 AD（ADAD）突变携带者是评估潜在的疾病修饰 Aβ 治疗效果的理想人群。
淀粉样蛋白假说的主要挑战包括认识到仅 Aβ 稳态失调不足以产生 AD 病理生理过程、Aβ 与认知障碍相关性差，以及针对 Aβ 靶向治疗的临床疗效不确定。ADAD 研究的挑战包括该疾病的罕见性和 ADAD 研究结果对更为常见的“散发性”迟发性 AD 的推广性的不确定性。
在这里进行了修改，以适用于 AD 的临床前阶段的淀粉样蛋白级联假说仍然需要与 tau 病和其他共病的发展和影响（包括神经炎症、血管损伤、突触核蛋白病等）相结合。
