A hypothesis is proposed to explain the pathogenesis of neurodegenerative disease and the diversity of its phenotypes. The hypothesis is based on seven main propositions: 1) neurodegenerative disease is associated with multiple risk factors, 2) age is the most important of the risk factors, 3) aging differentially affects neuroanatomical pathways, 4) degeneration of these pathways results in the formation of pathogenic proteins, 5) pathogenic proteins spread along anatomical pathways, 6) the phenotypes of familial and sporadic forms of disease are similar and 7) neurodegenerative disease is characterised by heterogeneity, overlapping phenotypes, and multiple pathology. It is hypothesised that most cases of neurodegenerative disease are multifactorial in which interactions between external environmental and internal genetic risk factors act cumulatively over a lifetime to determine the ‘allostatic load’ of an individual. The allostatic load determines the rate of neural aging and results in the differential breakdown of neuro-anatomical pathways influenced by their relative use or disuse during life. The consequence is the formation of one or more pathogenic proteins, some of which may exhibit ‘prion-like’ behaviour and propagate through the brain from initial sites of formation along neuro-anatomical pathways to affect connected brain regions. Variations in the pathological proteins formed and their anatomical spread are ultimately responsible for the clinical and patholo­gical diversity of disease phenotypes. Minimising the factors which contribute to the allostatic load over a lifetime and maximising cognitive and physical exercise may be necessary to reduce the incidence of neurodegenerative disease.

中文翻译：

---

什么原因导致神经退行性疾病？

提出了一个假设来解释神经退行性疾病的发病机理及其表型的多样性。该假设基于七个主要命题：1）神经退行性疾病与多种危险因素相关，2）年龄是最重要的危险因素，3）衰老对神经解剖学途径有不同的影响，4）这些途径的退化导致形成5）病原蛋白沿解剖途径传播，6）家族性和散发性疾病的表型相似，7）神经退行性疾病以异质性，重叠表型和多种病理学为特征。假设大多数神经退行性疾病是多因素的，其中外部环境和内部遗传危险因素之间的相互作用在一生中累积起作用，以确定“恒流负荷”。个人。静态负荷决定了神经衰老的速率，并导致神经解剖通路在生活中的相对使用或不使用的影响下，神经解剖通路的差异性分解。结果是形成一种或多种致病蛋白，其中一些可能表现出“ pr病毒样”。行为并沿着神经解剖路径从形成的初始部位在大脑中传播，从而影响相连的大脑区域。病理蛋白质的形成及其解剖分布的差异最终导致疾病表型的临床和病理学多样性。最小化在整个生命过程中造成同化力负荷的因素，并使认知和体育锻炼最大化，对于减少神经退行性疾病的发生可能是必要的。