Transcranial alternating current stimulation (tACS) at gamma frequency: an up-and-coming tool to modify the progression of Alzheimer's Disease

Abstract

The last decades have witnessed huge efforts devoted to deciphering the pathological mechanisms underlying Alzheimer's Disease (AD) and to testing new drugs, with the recent FDA approval of two anti-amyloid monoclonal antibodies for AD treatment. Beyond these drug-based experimentations, a number of pre-clinical and clinical trials are exploring the benefits of alternative treatments, such as non-invasive stimulation techniques on AD neuropathology and symptoms. Among the different non-invasive brain stimulation approaches, transcranial alternating current stimulation (tACS) is gaining particular attention due to its ability to externally control gamma oscillations. Here, we outline the current knowledge concerning the clinical efficacy, safety, ease-of-use and cost-effectiveness of tACS on early and advanced AD, applied specifically at 40 Hz frequency, and also summarise pre-clinical results on validated models of AD and ongoing patient-centred trials.

Keywords: Alzheimer’s disease; Brain waves; Early intervention; Gamma oscillations; Mild cognitive impairment; Network dysfunction; Neuromodulation; Non-invasive brain stimulation; Parvalbumin interneurons; Theranostic approach.

Fig. 1

40 Hz tACS as a potential therapy for AD. The left side of the figure illustrates the untreated, diseased state. The AD brain is marked by compromised gamma frequency oscillations and cognitive deficits. The pathological sequence commences with the excessive production of Aβ soluble oligomers, resulting in PV-IN dysfunction and subsequent dysregulation of the excitation (E) / inhibition (I) balance. The presence of excessive Aβ and the neuronal dysregulation instigate neuroinflammatory responses, leading to cerebral hypoperfusion and consequent brain hypometabolism. The interplay among E/I imbalance, neuroinflammation and hypoperfusion exacerbates Aβ oligomerization (indicated by gray dashed arrows), promoting a self-perpetuating cycle culminating in plaque and neurofibrillary tangle (NFT) formation. The pathological cascade reaches its peak with network disruption, characterized by the broad term “oscillopathy”. Conversely, the right side depicts the therapeutic potential of 40 Hz tACS. Diverse tACS protocols can be tailored to specific frequencies and electrode placements, contingent upon the targeted neural wave synchronization. Preliminary pre-clinical and clinical trials suggest that 40 Hz tACS restores the amplitude of gamma oscillations, synchronizing PV-IN activity and restoring E/I balance. Consequently, this can mitigate neuroinflammation, enhance cerebral perfusion and metabolism and facilitate a decrease in oligomer formation, overall reducing Aβ burden and tangle accumulation. Ultimately, interrupting the pathological cycle would lead to the reinstatement of neural network synchrony and cognitive enhancement. Red solid arrows denote the levels at which 40 Hz tACS is presumed to intervene to address the aforementioned pathological mechanisms, while green dashed arrows signify the improvements that can be elicited by tACS across the same pathological processes

Fig. 2

Cognitive impact of 40 Hz tACS in the AD murine hippocampus. The portrayal of the murine model of AD provides insights into the typical pathological features of AD, with a focus on the hippocampus (brain region pivotal for memory and cognition, commonly implicated in the early stages of the disease). The murine hippocampus exhibits significant signs of neuroinflammation, Aβ and tau accumulation, highlighting compromised neuronal networks and PV-IN activity. Subsequently, 40 Hz tACS reveals a series of improvements in terms of reduction in Aβ accumulation, enhanced cognitive functions, increased gamma power, and promotion of adult hippocampal neurogenesis. These outcomes suggest that 40 Hz tACS might positively impact brain physiology, delineating the connection between 40 Hz stimulation and the observed positive effects in the murine AD hippocampus, and offering fundamental insights into its potential therapeutic relevance for human AD. However, further exploration of other implicated brain regions and/or mechanisms involved is imperative to comprehend the holistic effects of 40 Hz tACS on AD pathology

Fig. 3

Spectrum of AD: biomarker trends and intervention options. The gradient bars describe the manifestation of the key hallmarks across the AD continuum, in which symptom severity increases throughout all the disease stages. Specifically, one of the earliest detectable aberrations include gamma wave disturbances, followed by significant plaque deposition, tau-mediated lesion processes and neurodegeneration, while cognitive function is relatively preserved in the early stages. Importantly, due to its safety and feasibility, 40 Hz tACS can be administered as early as the MCI stage to restore gamma waves, thus providing a key opportunity to modulate all other biomarkers. Similarly, the FDA-approved lecanemab can be administered early, during MCI and early AD to reduce the amyloid load. This time window provides a critical advantage for early treatment, and the combined usage of both approaches (tACS and lecanemab) might be highly beneficial. Alternatively, tACS can be applied alone, when patients are not eligible for pharmacological treatment. Of note, early treatment requires early diagnosis; in this framework, compared to the current diagnostic tools, EEG-tACS could represent an ideal strategy for future prompt intervention

Fig. 4

Mechanisms of large-scale gamma band synchronization in neural networks. The large-scale gamma band synchronization represents a powerful mechanism for integration and coordination of distant neurons. The firing of spatially distant neurons might show considerable delays due to axonal conduction and synaptic transmission. However, the relative phase of gamma oscillations in separated or within the same areas is cancelled, as in reality the firing of distant neurons does not show delay or is proximately zero (zero lag-phase synchrony). This synchronization mechanism is based on two main models, the first termed Inhibitory-Inhibitory (I-I), and the second Inhibitory-Excitatory (I-E). a The I-I model only consists of inhibitory interneurons (INs, IN1 marked blue and IN2 marked green), that are mutually inhibited via GABA_A receptors to quickly actualize zero-phase synchrony. When the first PV-IN fires, it can inhibit itself and also inhibit distant INs (blue bands). Likewise, the inhibition of the second PV-IN inhibits itself and the first PV-IN (green band). b The E-I model consists of excitatory pyramidal neurons (red) and inhibitory INs (blue). The short millisecond delay between the firing of the pyramidal neuron and the spike of the IN is consistent with monosynaptic excitation of the IN, which in turn activates a GABA_A receptor-mediated inhibition of the pyramidal cell (red band), that precedes pyramidal cell depolarization. In this way, the rhythmic activity of INs synchronizes the spiking of pyramidal cells, creating a window for action potential initiation in pyramidal cells. In this scenario, the fast excitation and the delayed feedback inhibition alternate, creating a cyclic oscillating trend that persists over time