Many models of disease progression in Alzheimer's disease (AD) have been proposed to help guide experimental design and aid the interpretation of results. Models focussing on the genetic evidence include the amyloid cascade (ACH) and presenilin (PSH) hypotheses and the amyloid precursor protein (APP) matrix approach (AMA), of which the ACH has held a dominant position for over two decades. However, the ACH has never been fully accepted and has not yet delivered on its therapeutic promise. We review the ACH, PSH and AMA in relation to levels of APP proteolytic fragments reported from AD-associated mutations in APP. Different APP mutations have diverse effects on the levels of APP proteolytic fragments. This evidence is consistent with at least three disease pathways that can differ between familial and sporadic AD and two pathways associated with cerebral amyloid angiopathy. We cannot fully evaluate the ACH, PSH and AMA in relation to the effects of mutations in APP as the APP proteolytic system has not been investigated systematically. The confounding effects of sequence homology, complexity of competing cleavages and antibody cross reactivities all illustrate limitations in our understanding of the roles these fragments and the APP proteolytic system as a whole in normal aging and disease play. Current experimental design should be refined to generate clearer evidence, addressing both aging and complex disorders with standardised reporting formats. A more flexible theoretical framework capable of accommodating the complexity of the APP proteolytic system is required to integrate available evidence.

中文翻译：

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了解突变在阿尔茨海默病中淀粉样蛋白前体蛋白中的作用。

已提出许多阿尔茨海默氏病（AD）疾病进展模型，以帮助指导实验设计并帮助解释结果。专注于遗传证据的模型包括淀粉样蛋白级联（ACH）和早老素（PSH）假说以及淀粉样蛋白前体蛋白（APP）基质方法（AMA），其中ACH占据了主导地位超过二十年。然而，ACH从未被完全接受并且尚未实现其治疗前景。我们回顾了与APP中AD相关突变报道的APP蛋白水解片段水平相关的ACH，PSH和AMA。不同的APP突变对APP蛋白水解片段的水平具有不同的影响。该证据与至少三种在家族性和散发性AD之间可能有所不同的疾病途径以及与脑淀粉样血管病相关的两种途径是一致的。由于尚未对APP的蛋白水解系统进行系统的研究，因此我们无法全面评估ACH，PSH和AMA与APP突变的影响有关。序列同源性，竞争性切割的复杂性和抗体交叉反应性的混杂影响，都说明了我们对这些片段和APP蛋白水解系统作为整体在正常衰老和疾病中的作用的理解的局限性。应该完善当前的实验设计，以产生更清晰的证据，以标准化的报告格式解决衰老和复杂疾病。