The Neurobiological Mechanisms of rTMS in Alzheimer's Disease

Impact of rTMS on Synaptic Plasticity in Patients with AD

Synaptic plasticity, defined as the ability of synapses to strengthen or weaken in response to increases or decreases in activity, is crucial for learning and memory. In Alzheimer’s disease, synaptic dysfunction and impaired synaptic plasticity have been identified as hallmark features. rTMS has been shown to enhance synaptic plasticity by modulating neurotransmitter release and promoting the expression of neurotrophic factors such as BDNF (brain-derived neurotrophic factor) and NGF (nerve growth factor) (Antonioni et al., 2025).

Mechanisms of Action

1. Neurotransmitter Modulation: High-frequency rTMS (HF-rTMS) increases the release of glutamate, the principal excitatory neurotransmitter, which is vital for inducing long-term potentiation (LTP), a cellular mechanism underlying learning. Conversely, low-frequency rTMS (LF-rTMS) has been associated with long-term depression (LTD), helping to recalibrate synaptic responses in hyperexcitable pathways (Antonioni et al., 2025).

2. Increased Neurotrophic Factor Levels: Studies have demonstrated that rTMS increases the levels of neurotrophic factors, which are critical for neuronal survival and synaptic plasticity. For instance, in animal models, HF-rTMS has been linked to enhanced production of BDNF, which supports synaptic integrity and plasticity (Antonioni et al., 2025).

3. Restoration of Excitation/Inhibition Balance: rTMS has been shown to restore the balance between excitatory and inhibitory neurotransmitter systems, particularly by modulating GABAergic circuits, which is crucial in preventing excitotoxicity associated with glutamate overactivity (Antonioni et al., 2025).

Role of Neuroinflammation in Alzheimer’s Disease and rTMS

Neuroinflammation plays a significant role in the pathogenesis of AD, contributing to synaptic dysfunction and neuronal loss. rTMS has been shown to exert anti-inflammatory effects, which may help mitigate the neuroinflammatory processes associated with AD.

Mechanisms of rTMS in Neuroinflammation

1. Reduction of Pro-inflammatory Cytokines: rTMS can decrease the release of pro-inflammatory cytokines and reduce microglial activation, thereby counteracting the neuroinflammatory response that exacerbates AD pathology (Antonioni et al., 2025).

2. Neuroprotective Effects: By enhancing neuroprotective factors and reducing oxidative stress, rTMS can potentially reverse some of the neurodegenerative changes seen in AD. This involves modulating the activity of signaling pathways that are critically involved in neuroinflammatory responses (Antonioni et al., 2025).

Effects of rTMS on Neurotransmitter Circuits in Alzheimer’s

The disruption of neurotransmitter systems, particularly cholinergic and glutamatergic pathways, is a significant feature of AD. rTMS has been shown to modulate these circuits effectively.

Cholinergic and Glutamatergic Circuits

1. Cholinergic Dysfunction: rTMS has been shown to enhance cholinergic signaling in the brain, which is crucial for memory and learning. Increased levels of acetylcholine (ACh) and modulation of acetylcholinesterase (AChE) activity have been observed following rTMS treatment (Antonioni et al., 2025).

2. Glutamatergic Pathways: The stimulation of glutamatergic pathways through rTMS helps restore synaptic plasticity and cognitive functions. By increasing glutamate release and improving NMDA receptor function, rTMS can enhance learning and memory processes (Antonioni et al., 2025).

Long-term Benefits of rTMS for Cognitive Function in AD

The cumulative evidence from clinical trials suggests that rTMS can lead to significant improvements in cognitive function among patients with AD. Studies show that patients receiving rTMS exhibit better performance in memory tests and improved daily functioning.

Clinical Efficacy

1. Cognitive Assessment: Clinical trials have demonstrated that rTMS can improve scores on cognitive assessments and daily living activities, indicating its potential as a therapeutic tool for managing cognitive decline in AD patients (Antonioni et al., 2025).

2. Durability of Effects: The cognitive improvements observed following rTMS treatment appear to be sustained over time, suggesting that rTMS may help slow the progression of cognitive impairments associated with AD (Antonioni et al., 2025).

Conclusion

In summary, repetitive transcranial magnetic stimulation presents a promising intervention for individuals with Alzheimer’s disease. By modulating synaptic plasticity, reducing neuroinflammation, and restoring neurotransmitter balance, rTMS has the potential to improve cognitive function and overall quality of life for AD patients.

References

1. Antonioni, A., Martorana, A., Santarnecchi, E., Hampel, H., & Koch, G. (2025). The neurobiological foundation of effective repetitive transcranial magnetic brain stimulation in Alzheimer’s disease. Alzheimer’s & Dementia, 21, e70337

2. Meyer, P. (2025). Insights on the neurocognitive mechanisms underlying hippocampus-dependent memory impairment in COVID-19. Scientific Reports, 15(1), 579. https://doi.org/10.1038/s41598-025-04166-2

3. Yang, Y., Yi, B., & Zhang, T. (2025). The impact of substance use disorder and drug transfer into breast milk: Implications for maternal and infant health. Pharmaceutics, 17(6), 719

4. Yousufzai, W., Heo, A., Gu, K., Sun, E., Lopez, G., Balamurali, S., … & McMahon, T. (2025). First episode of psychiatric and neuropsychiatric disease among patients infected with COVID‐19: A scoping review. Psychiatry Clin Neurosci Rep, 4, e70146

5. Michielse, S., Bakker, J., Lange, I., Batink, T., Goossens, L., Wichers, M., … & van Amelsvoort, T. (2023). Acceptance and Commitment Therapy and white matter plasticity in individuals with subclinical depression and psychotic experiences: A Randomised Controlled Trial. Neuroimage: Reports, 26, 100190. https://doi.org/10.1016/j.ynirp.2023.100190

FAQ

What is rTMS and how does it work for Alzheimer’s disease?

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that enhances neuronal activity and promotes synaptic plasticity. It works by using magnetic fields to stimulate nerve cells in specific areas of the brain, leading to improved cognitive functions and mitigating symptoms of Alzheimer’s disease.

Are there any side effects associated with rTMS?

rTMS is generally well-tolerated with minimal side effects, which may include mild headaches or scalp discomfort. Serious side effects are rare but can occur, so patients should be screened for contraindications before treatment.

How effective is rTMS in improving cognitive function in Alzheimer’s patients?

Clinical studies have shown that rTMS can lead to significant improvements in cognitive assessments and daily functioning in Alzheimer’s patients, potentially slowing the progression of cognitive decline.

How long do the effects of rTMS last?

The cognitive improvements from rTMS treatments can be sustained over time, although individual responses may vary. Maintenance sessions may help prolong the benefits.

Is rTMS suitable for all Alzheimer’s patients?

While rTMS is promising, suitability depends on individual patient factors, including the severity of the disease, medical history, and specific symptoms. It’s essential to consult with a healthcare professional to determine the appropriateness of rTMS for each patient.