Although Alzheimer's disease (AD) was described over a century ago, there are no effective approaches to its prevention and treatment. Such a slow progress is explained, at least in part, by our incomplete understanding of the mechanisms underlying the pathogenesis of AD. Here, I champion a hypothesis whereby AD is initiated on a disruption of the blood-brain barrier (BBB) caused by either genetic or non-genetic risk factors. The BBB disruption leads to an autoimmune response against pyramidal neurons located in the allo- and neocortical structures involved in memory formation and storage. The response caused by the adaptive immune system is not strong enough to directly kill neurons but may be sufficient to make them selectively vulnerable to neurofibrillary pathology. This hypothesis is based on the recent data showing that memory formation is associated with epigenetic chromatin modifications and, therefore, may be accompanied by expression of memory-specific proteins recognized by the immune system as "non-self" antigens. The autoimmune hypothesis is testable, and I discuss potential ways for its experimental and clinical verification. If confirmed, this hypothesis can radically change therapeutic approaches to AD prevention and treatment.

中文翻译：

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阿尔茨海默病：从淀粉样蛋白到自身免疫假说。

尽管阿尔茨海默病 (AD) 早在一个多世纪前就已有描述，但目前还没有有效的预防和治疗方法。如此缓慢的进展至少部分是由于我们对 AD 发病机制的不完全了解所致。在这里，我支持一个假设，即 AD 是由遗传或非遗传风险因素引起的血脑屏障 (BBB) 破坏引发的。BBB 破坏导致对位于同种异体和新皮质结构中的锥体神经元的自身免疫反应，这些神经元参与记忆形成和存储。适应性免疫系统引起的反应不足以直接杀死神经元，但可能足以使它们选择性地易受神经原纤维病理的影响。这一假设基于最近的数据，表明记忆形成与表观遗传染色质修饰有关，因此可能伴随着被免疫系统识别为“非自身”抗原的记忆特异性蛋白质的表达。自身免疫假说是可检验的，我讨论了其实验和临床验证的潜在方法。如果得到证实，这一假设可以从根本上改变 AD 预防和治疗的治疗方法。