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首页> 外文期刊>Journal of Molecular Psychiatry >Unified theory of Alzheimer’s disease (UTAD): implications for prevention and curative therapy
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Unified theory of Alzheimer’s disease (UTAD): implications for prevention and curative therapy

机译：阿尔茨海默氏病（UTAD）统一理论：对预防和治疗的意义

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The aim of this review is to propose a Unified Theory of Alzheimer’s disease (UTAD) that integrates all key behavioural, genetic and environmental risk factors in a causal chain of etiological and pathogenetic events. It is based on three concepts that emanate from human’s evolutionary history: (1) The grandmother-hypothesis (GMH), which explains human longevity due to an evolutionary advantage in reproduction by trans-generational transfer of acquired knowledge. Consequently it is argued that mental health at old-age must be the default pathway of humans’ genetic program and not development of AD. (2) Therefore, mechanism like neuronal rejuvenation (NRJ) and adult hippocampal neurogenesis (AHN) that still function efficiently even at old age provide the required lifelong ability to memorize personal experiences important for survival. Cumulative evidence from a multitude of experimental and epidemiological studies indicate that behavioural and environmental risk factors, which impair productive AHN, result in reduced episodic memory performance and in reduced psychological resilience. This leads to avoidance of novelty, dysregulation of the hypothalamic–pituitary–adrenal (HPA)-axis and cortisol hypersecretion, which drives key pathogenic mechanisms of AD like the accumulation and oligomerization of synaptotoxic amyloid beta, chronic neuroinflammation and neuronal insulin resistance. (3) By applying to AHN the law of the minimum (LOM), which defines the basic requirements of biological growth processes, the UTAD explains why and how different lifestyle deficiencies initiate the AD process by impairing AHN and causing dysregulation of the HPA-axis, and how environmental and genetic risk factors such as toxins or ApoE4, respectively, turn into disease accelerators under these unnatural conditions. Consequently, the UTAD provides a rational strategy for the prevention of mental decline and a system-biological approach for the causal treatment of AD, which might even be curative if the systemic intervention is initiated early enough in the disease process. Hence an individualized system-biological treatment of patients with early AD is proposed as a test for the validity of UTAD and outlined in this review.
机译：本文的目的是提出一个统一的阿尔茨海默氏病理论（UTAD），该理论将所有关键的行为，遗传和环境风险因素整合到病因和病因事件的因果链中。它基于源自人类进化史的三个概念：（1）祖母假说（GMH），它解释了人类的长寿，这归因于获得知识的跨代转移在繁殖中的进化优势。因此，有人认为，老年人的心理健康必须是人类遗传程序的默认途径，而不是AD的发展。 （2）因此，即使在老年时仍能有效发挥作用的机制，如神经元年轻化（NRJ）和成人海马神经发生（AHN），提供了所需的终身记忆能力，以记忆对生存至关重要的个人经历。来自大量实验和流行病学研究的累积证据表明，会损害生产性AHN的行为和环境风险因素会导致情节性记忆表现下降，以及心理弹性下降。这就避免了新颖性，下丘脑-垂体-肾上腺（HPA）轴失调和皮质醇分泌过多，从而驱动了AD的关键致病机制，例如突触毒性淀粉样β的积累和低聚，慢性神经炎症和神经元胰岛素抵抗。 （3）通过向AHN应用定义生物生长过程基本要求的最低定律（LOM），UTAD解释了不同的生活方式缺陷为何以及如何通过损害AHN并导致HPA轴失调而引发AD过程。以及环境和遗传风险因素（例如毒素或ApoE4）如何分别在这些非自然条件下转变为疾病的促进剂。因此，UTAD为预防精神衰弱提供了合理的策略，并且为AD的因果治疗提供了系统生物学的方法，如果在疾病过程中足够早地进行系统干预，这甚至可以治愈。因此，建议对AD早期患者进行个体化的系统生物学治疗，作为UTAD有效性的测试，并在本综述中进行了概述。

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