Kurakin Alexei, Bredesen Dale E
Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Aging (Albany NY). 2020 Sep 21;12(18):17815-17844. doi: 10.18632/aging.103883.
Ineffective results of clinical trials of over 200 anti-Alzheimer's drug candidates, with a 99.6% attrition rate, suggest that the current paradigm of Alzheimer's disease (AD) may be incomplete, necessitating exploration of alternative and complementary frameworks.Using algorithms for hypothesis independent search and expert-assisted synthesis of heterogeneous data, we attempted to reconcile multimodal clinical profiles of early-stage AD patients and accumulated research data within a parsimonious framework. Results of our analysis suggest that Alzheimer's may not be a brain disease but a progressive system-level network disorder, which is driven by chronic network stress and dyshomeostasis. The latter can be caused by various endogenous and exogenous factors, such as chronic inflammatory conditions, infections, vascular dysfunction, head trauma, environmental toxicity, and immune disorders. Whether originating in the brain or on the periphery, chronic stress, toxicity, and inflammation are communicated to the central nervous system (CNS) via humoral and neural routes, preferentially targeting high-centrality regulatory nodes and circuits of the nervous system, and eventually manifesting as a neurodegenerative CNS disease.In this report, we outline an alternative perspective on AD as a systems network disorder and discuss biochemical and genetic evidence suggesting the central role of chronic tissue injury/dyshomeostasis, innate immune reactivity, and inflammation in the etiopathobiology of Alzheimer's disease.
200多种抗阿尔茨海默病候选药物的临床试验结果不佳，淘汰率达99.6%，这表明目前的阿尔茨海默病（AD）范式可能并不完整，因此有必要探索其他补充框架。我们使用假设独立搜索算法和专家辅助的异构数据合成方法，试图在一个简洁的框架内协调早期AD患者的多模态临床特征和积累的研究数据。我们的分析结果表明，阿尔茨海默病可能不是一种脑部疾病，而是一种由慢性网络应激和内环境失调驱动的进行性系统级网络障碍。后者可能由各种内源性和外源性因素引起，如慢性炎症、感染、血管功能障碍、头部创伤、环境毒性和免疫紊乱。无论是起源于大脑还是外周，慢性应激、毒性和炎症都会通过体液和神经途径传递到中枢神经系统（CNS），优先靶向神经系统的高中心性调节节点和回路，并最终表现为一种神经退行性CNS疾病。在本报告中，我们概述了将AD视为系统网络障碍的另一种观点，并讨论了生化和遗传学证据，这些证据表明慢性组织损伤/内环境失调、先天免疫反应和炎症在阿尔茨海默病的病因生物学中起核心作用。
