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Review
. 2025 Jun;21(6):e70337.
doi: 10.1002/alz.70337.

The neurobiological foundation of effective repetitive transcranial magnetic brain stimulation in Alzheimer's disease

Annibale Antonioni  1 , Alessandro Martorana  2 , Emiliano Santarnecchi  3 , Harald Hampel  4 , Giacomo Koch  1   5   6
Affiliations
Review

The neurobiological foundation of effective repetitive transcranial magnetic brain stimulation in Alzheimer's disease

Annibale Antonioni et al. Alzheimers Dement. 2025 Jun.

Abstract

Noninvasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS), are promising candidate therapeutics for Alzheimer's disease (AD). We review the evidence supporting the fundamental mechanisms of action of rTMS treatments in AD. rTMS exerts profound effects at different neurobiological and systems neurophysiological levels. By engaging distinct pre- and postsynaptic structures within the stimulated neural network, it directly or indirectly influences various cellular and molecular components. In AD, rTMS influences synaptic plasticity, inducing lasting structural changes and broad reorganization of functional and structural connectivity at the macroscale level. Importantly, it modulates neurotransmitter circuits characteristically disrupted in AD and restores the excitation/inhibition balance by targeting glutamatergic and γ-aminobutyric acid (GABA)ergic pathways. Moreover, rTMS increases neurotrophic factors, counteracts amyloid and tau accumulation, and mitigates neuroinflammation by reducing microglial activation and pro-inflammatory cytokines release. Therefore, maturing preclinical evidence could guide future precision medicine therapeutic strategies based on personalized NIBS in AD patients. HIGHLIGHTS: Noninvasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS), are promising candidate therapeutics for Alzheimer's disease (AD). rTMS modulates neuroplasticity, neurotransmission, and neuroinflammation. Preclinical research shows disease-specific neurobiological effects of rTMS in AD. Promising data from AD patients suggest the translatability of animal model results. Preclinical data may guide precision medicine strategies through personalized NIBS.

Keywords: Alzheimer's disease (AD); animal models; noninvasive brain stimulation (NIBS); pathological cascade; plasticity; preclinical research; repetitive transcranial magnetic stimulation (rTMS); transcranial magnetic stimulation (TMS).

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Conflict of interest statement

Annibale Antonioni declares no conflicts of interest related to this manuscript. Giacomo Koch is scientific co‐founder and holds stocks of Sinaptica Therapeutics. Giacomo Koch has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Epitech, Roche, Novo Nordisk. Giacomo Koch and Alessandro Martorana have the following patent issued: Combination drug formulations including rotigotine and an acetylcholinesterase inhibitor for the treatment of neurodegenerative diseases (n. 20230381512); Giacomo Koch and Emiliano Santarnecchi have the following patent issued: Systems and methods for providing personalized targeted non‐invasive stimulation to a brain network (n. 11998740). GK reports grants from BrighFocus Foundation, Epitech, Alzheimer's Drug Discovery Foundation (ADDF), Italian Ministry of Health and non‐financial support from UCB Pharma outside the submitted work. Alessandro Martorana reports grants from Alzheimer's Drug Discovery Foundation, BrighFocus Foundation, Italian Ministry of Health and non‐financial support from UCB Pharma outside the submitted work.

Harald Hampel is an employee of Eisai Inc.; however, this article does not represent the opinion of Eisai. His contribution to this article reflects only and exclusively his academic and scientific expertise and was initiated during an academic appointment at Sorbonne University, Paris, France. He serves as a Reviewing Editor and previously as Senior Associate Editor for the journal Alzheimer's & Dementia, the journal of the Alzheimer's Association.

Harald Hampel is inventor of 11 patents and has received no royalties:

1. In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388

2. In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784

3. Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300

4. In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463

5. In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286

6. In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822

7. In Vitro Method for The Diagnosis of Neurodegenerative Diseases Patent Number: 7547553

8. CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797

9. In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966

10. Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921

11. Method for diagnosis of dementias and neuroinflammatory diseases based on an increased level of procalcitonin in cerebrospinal fluid: Publication number: United States Patent 10921330. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Mechanisms of rTMS‐induced neuroplasticity and therapeutic effects in AD. rTMS promotes neuroplasticity and cognitive improvement by modulating key pathological mechanisms in AD. Indeed, in animal models, rTMS enhances synaptic function by increasing the expression of structural synaptic proteins, reducing neuroinflammatory processes (e.g., by promoting glutamate reuptake and preventing microglial activation), upregulating growth factors, and increasing neurotransmitter synthesis. It also decreases amyloid production and deposition while facilitating the clearance of toxic aggregates, ultimately improving performance and behavior. Accordingly, by acting on these mechanisms, also in AD patients rTMS fosters cortical plasticity, restores LTP‐like mechanisms in key brain areas, strengthens structural and functional brain connectivity, and preserves the integrity of gray matter. These effects contribute to enhanced metabolism in damaged brain regions and improved cognitive functions, highlighting rTMS as a promising neuromodulatory intervention in AD patients. AD, Alzheimer's disease; LTP, long‐term potentiation; rTMS, repetitive transcranial magnetic stimulation. Created with BioRender.com.
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