Identifying effective treatments for Alzheimer’s disease (AD) has proven challenging and has instigated a shift in AD research focus toward the earliest disease-initiating cellular mechanisms. A key insight has been an increase in soluble Aβ oligomers in early AD that is causally linked to neuronal and circuit hyperexcitability. However, other accumulating AD-related peptides and proteins, including those derived from the same amyloid precursor protein, such as Aη or sAPPα, and autonomously, such as tau, exhibit surprising opposing effects on circuit dynamics. We propose that the effects of these on neuronal circuits have profound implications for our understanding of disease complexity and heterogeneity and for the development of personalized diagnostic and therapeutic strategies in AD. Here, we highlight important peptide-specific mechanisms of dynamic pathological disequilibrium of cellular and circuit activity in AD and discuss approaches in which these may be further understood, and theoretically and experimentally leveraged, to elucidate AD pathophysiology.

事实证明，找到有效的阿尔茨海默氏病（AD）治疗方法具有挑战性，并已促使AD研究重点转向最早的疾病引发细胞机制。一个关键的见解是早期AD中可溶性Aβ低聚物的增加，这与神经元和电路的过度兴奋性有因果关系。然而，其他累积的与AD相关的肽和蛋白质，包括衍生自相同淀粉样前体蛋白质的那些，例如Aη或sAPPα，以及自主产生的，例如tau，对电路动力学表现出令人惊讶的相反影响。我们建议这些对神经元回路的影响对我们对疾病复杂性和异质性的理解以及对AD个性化诊断和治疗策略的发展具有深远的影响。这里，