The revised criteria for diagnosis and staging of Alzheimer's disease (AD)¹ update the 2018 Research Framework and reaffirm the concept of AD as a primary biological entity. These new criteria focus on biomarkers that represent distinct pathological processes, measurable in living individuals using neuroimaging and biofluid assays to track disease course. Specifically, the framework proposes three categories: core biomarkers of AD neuropathologic change, non-specific biomarkers of AD pathogenesis that are also involved in other brain diseases, and biomarkers of common non-AD co-pathologies.

The pathological changes in AD begin years before the manifestation of clinical symptoms² that emerge when brain damage surpasses an individually determined threshold. This latter is influenced by the individual cognitive reserve and brain resilience to abnormal protein deposition.

Despite the substantial advances outlined in these criteria, a significant gap remains between the biochemical and the structural changes driving AD pathogenesis and the corresponding dysfunction of neural networks which is correlated with cognitive impariment. Recent studies indicate that this gap can, at least partially, be filled by techniques that allow for the in vivo functional evaluation of cortical circuit excitability and plasticity. Over the past two decades, non-invasive neurophysiological techniques, namely transcranial magnetic stimulation (TMS) and electroencephalography (EEG), have been used as biomarkers of synaptic dysfunction and seem promising for evaluating the N (injury, dysfunction, or degeneration of neuropil) category.

In these updated criteria, the role of synaptic loss and dysfunction in neurodegeneration is highlighted, along with possible evaluation tools including positron emission tomography imaging, fluid biomarkers, and EEG. We would like to suggest that TMS may be an integral part of these tools, as TMS-based measures have achieved a significant level of maturity, offering insights into neuroplasticity and cortical connections at the level of specific neurotransmitters (Figure 1). These measures are becoming increasingly valuable for the characterization and differential diagnosis of dementia.³

Notably, some researchers consider AD a “synaptopathy,” because synaptic dysfunction, driven primarily by amyloid—especially amyloid beta oligomers—and tau deposition, is detected in the early stage of the disease, preceding neurodegeneration and atrophy in the neocortex.⁴

In support of this notion there is evidence that synaptic dysfunction correlates more closely with clinical symptoms than with pathological burden⁵ and that altered synaptic function plays a key role in the clinical symptom heterogeneity of AD. Indeed, it is well documented that patients with similar levels of pathological burden can exhibit different degrees of cognitive impairment. This variability is thought to arise from individual compensatory mechanisms to brain damage, such as neural networks remodeling and plasticity changes, which, unsurprisingly, occur at the synaptic level.

In this context, TMS might also be useful as a tool for monitoring disease progression. In the early stages of AD, the neural network disruption, the subsequent excitation/inhibition imbalance in the neocortex, and the increase of cortical excitability can be evidenced by the reduction of motor thresholds.⁶ As AD advances, various neurotransmitter circuits undergo alterations and these changes can be monitored through TMS protocols. For instance, deficit in central cholinergic circuit activity can be assessed in the AD early stage using a paired-pulse TMS protocol called short-latency afferent inhibition (SAI).⁷ Notably, administration of anticholinesterase inhibitors, L-dopa, or dopamine agonists restore SAI.⁷ Also, GABAA activity, tested by the paired-pulse TMS protocol short-interval intracortical inhibition (SICI), is reduced in AD patients with longer disease duration,⁸ while there is an increase of glutamatergic activity, as tested by the intracortical facilitation (ICF) protocol, even though data regarding the latter are more debated.^{6, 7} These measures might also assist in the differential diagnosis of dementia, as each form of dementia exhibits a distinct neurophysiological signature.⁶ Deficits in synaptic plasticity, including impaired long-term potentiation (LTP) and enhanced long-term depression (LTD, particularly in the hippocampus) have also been shown, mostly in mouse models, to play a critical role in AD.⁹ These synaptic abnormalities are associated with cognitive deficits and may underlie the epileptiform activity often observed in patients.⁹ Repetitive TMS (rTMS) protocols have indeed provided evidence of impaired LTP-like plasticity in the human motor cortex and rTMS has been shown to improve cognitive performance in AD patients.¹⁰

In real-world settings, predicting the progression of neurodegeneration, starting from the subjective complaint of cognitive impairment (CI) to mild CI and dementia, continues to be a challenge. Additionally, no biomarkers exist that can reflect the effects of therapeutic interventions in real time, as structural pathological changes take time to reverse. Neurophysiological tools offer significant potential as monitoring instruments due to their excellent time resolution, broad availability, and cost effectiveness.

We are entering a new era in the management of dementia, in which, thanks to a better understanding and greater accessibility of biomarkers, the diagnostic process has become more objective. These biomarkers allow for a precise characterization of the pathological profile of the individual affected by AD. In this context, multimodal assessment, which provides valuable information for a better-informed diagnosis and staging of AD, could be further strengthened by the inclusion of neurophysiological tools like TMS and EEG.

修订后的阿尔茨海默病 （AD） 诊断和分期标准1 更新了 2018 年研究框架，并重申了 AD 作为主要生物实体的概念。这些新标准侧重于代表不同病理过程的生物标志物，可以使用神经影像学和生物流体检测在活体个体中测量以跟踪病程。具体来说，该框架提出了三类：AD 神经病理变化的核心生物标志物、也涉及其他脑部疾病的 AD 发病机制的非特异性生物标志物，以及常见非 AD 联合病理的生物标志物。

AD 的病理变化在临床症状² 出现之前几年就开始了，当脑损伤超过个人确定的阈值时，就会出现这些症状。后者受个体认知储备和大脑对异常蛋白质沉积的弹性的影响。

尽管这些标准概述了实质性进展，但驱动 AD 发病机制的生化和结构变化以及与认知障碍相关的神经网络的相应功能障碍之间仍然存在重大差距。最近的研究表明，这一空白至少可以部分地通过允许对皮层回路兴奋性和可塑性进行体内功能评估的技术来填补。在过去的二十年里，非侵入性神经生理学技术，即经颅磁刺激 （TMS） 和脑电图 （EEG），已被用作突触功能障碍的生物标志物，并且似乎有望评估 N（神经细胞损伤、功能障碍或变性）类别。

在这些更新的标准中，强调了突触丢失和功能障碍在神经退行性变中的作用，以及可能的评估工具，包括正电子发射断层扫描成像、液体生物标志物和脑电图。我们想建议 TMS 可能是这些工具不可或缺的一部分，因为基于 TMS 的测量已经达到了相当的成熟度，在特定神经递质的水平上提供了对神经可塑性和皮层连接的见解（图 1）。这些措施对于痴呆的表征和鉴别诊断越来越有价值。³

值得注意的是，一些研究人员认为 AD 是一种“突触病”，因为主要由淀粉样蛋白（尤其是淀粉样蛋白 β 寡聚体）和 tau 沉积驱动的突触功能障碍是在疾病的早期阶段检测到的，先于神经退行性变和新皮层萎缩。⁴

支持这一观点，有证据表明，突触功能障碍与临床症状的相关性比与病理负担的相关性更密切⁵，并且突触功能改变在 AD 的临床症状异质性中起关键作用。事实上，有充分的证据表明，具有相似病理负担水平的患者可以表现出不同程度的认知障碍。这种可变性被认为是由脑损伤的个体代偿机制引起的，例如神经网络重塑和可塑性变化，不出所料，这些变化发生在突触水平。

在这种情况下，TMS 也可能可用作监测疾病进展的工具。在 AD 的早期阶段，神经网络破坏、随后新皮层的兴奋/抑制不平衡以及皮层兴奋性的增加可以通过运动阈值的降低来证明。⁶ 随着 AD 的进展，各种神经递质回路发生改变，这些变化可以通过 TMS 协议进行监测。例如，在 AD 早期阶段，可以使用称为短潜伏期传入抑制 （SAI） 的配对脉冲 TMS 方案来评估中枢胆碱能回路活性的缺陷。⁷ 值得注意的是，抗胆碱酯酶抑制剂、L-多巴或多巴胺激动剂的给药可恢复 SAI。⁷ 此外，通过配对脉冲 TMS 方案短间隔皮层内抑制 （SICI） 测试的 GABAA 活性在病程较长的 AD 患者中降低，⁸ 而谷氨酸能活性增加，如皮层内促进 （ICF） 方案所测试的那样，尽管关于后者的数据更具争议。^6、7这些措施也可能有助于痴呆的鉴别诊断，因为每种形式的痴呆都表现出独特的神经生理学特征。⁶ 突触可塑性缺陷，包括长期增强受损 （LTP） 和增强的长期抑制 （LTD，尤其是在海马体中），也已被证明在 AD 中起关键作用，主要在小鼠模型中。^这些突触异常与认知缺陷有关，可能是患者经常观察到的癫痫样活动的基础。⁹ 重复 TMS （rTMS） 方案确实提供了人类运动皮层中 LTP 样可塑性受损的证据，并且 rTMS 已被证明可以改善 AD 患者的认知能力。¹⁰

在现实世界中，预测神经退行性疾病的进展，从认知障碍 （CI） 的主观抱怨到轻度 CI 和痴呆，仍然是一个挑战。此外，不存在可以实时反映治疗干预效果的生物标志物，因为结构病理变化需要时间来逆转。神经生理学工具由于其出色的时间分辨率、广泛的可用性和成本效益，具有作为监测仪器的巨大潜力。

我们正在进入痴呆管理的新时代，在这个时代，由于对生物标志物的更好理解和更大可及性，诊断过程变得更加客观。这些生物标志物可以精确表征受 AD 影响的个体的病理特征。在这种情况下，多模式评估为更明智的 AD 诊断和分期提供了有价值的信息，可以通过纳入 TMS 和 EEG 等神经生理学工具来进一步加强。