Restoring Theta–Gamma coupling in Alzheimer's disease: Toward network-based neuromodulation - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Neurotherapeutics . 2026 Apr 9;23(3):e00901. doi: 10.1016/j.neurot.2026.e00901 Search in PMC Search in PubMed View in NLM Catalog Add to search Restoring Theta–Gamma coupling in Alzheimer's disease: Toward network-based neuromodulation Shixie Jiang Shixie Jiang 1 Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, USA Find articles by Shixie Jiang 1 Author information Article notes Copyright and License information 1 Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, USA Received 2026 Mar 26; Accepted 2026 Mar 26; Collection date 2026 Apr. Keywords: Alzheimer’s disease, Neural oscillations, Theta–gamma coupling, Neuromodulation, Brain stimulation, Cognition © 2026 The Author(s) This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). PMC Copyright notice PMCID: PMC13091500 PMID: 41962506 See " A compound pulsed magnetic field achieves superior cognitive benefits against Alzheimer's disease progression via multi-level restoration of neural oscillations and cerebral perfusion ", e00887. For decades, therapeutic strategies for Alzheimer's disease (AD) have largely focused on the accumulation and clearance of amyloid-β and other molecular pathologies. Yet growing evidence suggests that the clinical manifestations of AD reflect not only protein aggregation but also profound disruptions in large-scale neural network dynamics [ 1 ]. Long before significant neuronal loss occurs, alterations in brain oscillatory activity emerge across hippocampal and cortical circuits critical for memory. These oscillatory abnormalities, particularly disruptions in the coordination between theta and gamma rhythms, are increasingly recognized as key contributors to cognitive impairment in AD [ 2 ]. As a result, interest has grown in therapeutic approaches that directly target neural circuit dysfunction rather than solely downstream molecular pathology. In the March issue of Neurotherapeutics , Wang and colleagues present an intriguing approach to this problem by using a compound pulsed magnetic field (cPMF) designed to mimic cross-frequency interactions between theta and gamma rhythms [ 3 ]. In the 5xFAD mouse model of AD, the authors demonstrate that cPMF stimulation improves cognitive performance and restores hippocampal oscillatory dynamics more effectively than single-frequency stimulation. Specifically, the intervention enhanced theta–gamma phase-amplitude coupling (PAC), increased cerebral blood flow in cortical regions, reduced amyloid-β burden, and altered the expression of genes involved in synaptic plasticity, cholinergic signaling, and glymphatic function. Together, these findings suggest that magnetic stimulation patterns designed to engage endogenous oscillatory architecture may produce multi-level restorative effects in AD-related brain dysfunction. The focus on theta–gamma coupling is particularly notable. In hippocampal and cortical circuits, theta oscillations provide a temporal scaffold within which faster gamma activity organizes the sequential firing of neuronal assemblies [ 4 , 5 ]. This nested oscillatory structure is believed to support fundamental cognitive processes such as working memory, episodic encoding, and information transfer across distributed brain networks [ 6 , 7 ]. Disruption of this coupling has been observed in both animal models of AD and in human studies of mild cognitive impairment and dementia [ 2 , 8 ]. Importantly, alterations in oscillatory coordination may arise early in the disease process, potentially preceding overt neurodegeneration [ 9 , 10 ]. From this perspective, restoring physiologic patterns of neural synchrony represents a compelling strategy for modifying the functional consequences of AD-related pathology. Efforts to therapeutically modulate brain rhythms have gained momentum in recent years. Sensory stimulation at gamma frequencies has been shown to reduce amyloid deposition and modulate microglial activity in animal models, while non-invasive brain stimulation techniques, including transcranial alternating current stimulation and transcranial magnetic stimulation, have demonstrated the capacity to entrain cortical oscillations in humans [ 11 , 12 ]. Most of these approaches, however, target single oscillatory frequencies. The strategy employed by Wang et al. differs in an important way: their compound stimulation pattern attempts to replicate cross-frequency interactions that naturally occur in memory circuits. By embedding gamma-frequency activity within a theta-frequency framework, cPMF stimulation may more closely approximate the temporal organization of neural activity that supports cognitive processing. Another intriguing aspect of the study is the convergence of electrophysiologic, vascular, and molecular findings. The authors report increases in cortical perfusion and changes in the expression of genes associated with synaptic plasticity and neuroinflammatory pathways following stimulation. These observations raise the possibility that modulation of network activity could influence multiple downstream biological processes relevant to AD pathology. At the same time, the precise mechanisms linking oscillatory restoration to these molecular and vascular changes remain uncertain. For example, the relationship between improved cerebral blood flow, AQP4 expression, and potential glymphatic clearance of amyloid will require further experimental investigation. As with many preclinical neuromodulation studies, several limitations warrant consideration. The electrophysiologic recordings were performed under resting conditions rather than during active cognitive tasks, leaving open questions about how stimulation influences task-dependent network dynamics. Sample sizes for some experimental measures were modest, and correlations between oscillatory metrics and behavioral outcomes were necessarily conducted at the group level. Moreover, translating stimulation paradigms developed in rodent models to human neurostimulation presents substantial technical and physiological challenges. Despite these challenges, the work by Wang and colleagues contributes to a growing body of evidence suggesting that AD may be amenable to therapeutic strategies aimed at restoring network-level brain function. Rather than focusing exclusively on molecular pathology, such approaches seek to re-establish the rhythmic coordination of neuronal activity that underlies cognition. If successful, interventions that modulate oscillatory coupling could complement existing pharmacologic therapies and potentially open new avenues for circuit-based treatments of neurodegenerative disease. Future work will need to determine whether stimulation paradigms designed to restore cross-frequency coupling can be safely and effectively translated to human neuromodulation technologies. Advances in neuroimaging and electrophysiologic biomarkers may allow investigators to directly measure network responses to stimulation and guide individualized treatment protocols. Ultimately, the emerging convergence between systems neuroscience and neuromodulation raises the possibility that targeting the brain's intrinsic rhythms may become an important component of next-generation therapies for Alzheimer's disease. Author contributions Dr. Jiang was responsible all activities involved in this commentary, including conception, writing, editing, organization, and submission of the final product. Declaration of generative AI and AI-assisted technologies in the writing process No AI or AI-assisted technology was utilized in the conduct of this commentary, the writing of the manuscript, or during the revision process. Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Jiang serves as an Associate Editor of General Hospital Psychiatry (Elsevier) and receives an honorarium for his work as an Editor. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References 1. Palop J.J., Mucke L. 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