Synaptic loss is the best correlate of cognitive deficits in Alzheimer’s disease (AD). Extensive experimental evidence also indicates alterations of synaptic properties at the early stages of disease progression, before synapse loss and neuronal degeneration. A majority of studies in mouse models of AD have focused on post-synaptic mechanisms, including impairment of long-term plasticity, spine structure and glutamate receptor-mediated transmission. Here we review the literature indicating that the synaptic pathology in AD includes a strong presynaptic component. We describe the evidence indicating presynaptic physiological functions of the major molecular players in AD. These include the amyloid precursor protein (APP) and the two presenilin (PS) paralogs PS1 or PS2, genetically linked to the early-onset form of AD, in addition to tau which accumulates in a pathological form in the AD brain. Three main mechanisms participating in presynaptic functions are highlighted. APP fragments bind to presynaptic receptors (e.g. nAChRs and GABA_B receptors), presenilins control Ca²⁺ homeostasis and Ca²⁺-sensors, and tau regulates the localization of presynaptic molecules and synaptic vesicles. We then discuss how impairment of these presynaptic physiological functions can explain or forecast the hallmarks of synaptic impairment and associated dysfunction of neuronal circuits in AD. Beyond the physiological roles of the AD-related proteins, studies in AD brains also support preferential presynaptic alteration. This review features presynaptic failure as a strong component of pathological mechanisms in AD.

突触丢失是阿尔茨海默病 (AD) 中认知缺陷的最佳关联因素。大量的实验证据还表明，在疾病进展的早期阶段，在突触丧失和神经元变性之前，突触特性会发生改变。对 AD 小鼠模型的大多数研究都集中在突触后机制上，包括长期可塑性、脊柱结构和谷氨酸受体介导的传递受损。在这里，我们回顾了表明 AD 中的突触病理学包括强突触前成分的文献。我们描述了表明 AD 中主要分子参与者的突触前生理功能的证据。这些包括淀粉样前体蛋白 (APP) 和两个早老素 (PS) 旁系同源物 PS1 或 PS2，它们与早发性 AD 有遗传联系，除了在 AD 大脑中以病理形式积累的 tau。突出了参与突触前功能的三个主要机制。APP 片段与突触前受体（例如 nAChRs 和 GABA_B受体），早老素控制 Ca ²⁺稳态和 Ca ²⁺传感器，tau 调节突触前分子和突触小泡的定位。然后我们讨论这些突触前生理功能的损伤如何解释或预测 AD 中突触损伤和相关神经元回路功能障碍的标志。除了 AD 相关蛋白的生理作用外，对 AD 大脑的研究也支持优先突触前改变。本综述将突触前衰竭作为 AD 病理机制的一个重要组成部分。