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Preliminary Effect of Transcranial Electrical Stimulation on Protein Clearance in Patients with Alzheimer’s Disease

Novel brain stimulation therapy for Alzheimer’s disease

Boston, MA, USA – Alzheimer’s disease (AD) incidence is constantly increasing worldwide and patients have limited therapeutic options, that ultimately are not able to stop the cognitive decline. A recent study, published in the Journal of Alzheimer’s Disease, has found preliminary results of clearance of the toxic proteins that accumulates in the brain of patients with AD after 1 month of noninvasive electrical treatment. Results were paralleled by an increase in fast oscillatory brain activity in the so-called Gamma frequency band, usually decreased in patients with AD.

Emiliano Santarnecchi, PhD, director of the Precision Neuroscience and Neuromodulation program at the Gordon Center for Medical Imaging at the Massachusetts General Hospital (MGH) and Associate Professor of Radiology at Harvard Medical School (HMS) in Boston (MA, USA), was the Principal Investigator of the study performed at the Gordon Center for Medical Imaging at MGH and the Berenson-Allen Center for Noninvasive Brain Stimulation at Beth Israel Deaconess Medical Center (BIDMC) in Boston. The team at MGH also included Georges El Fahkri, PhD, Alpert Professor of Radiology at HMS and director of the Gordon Center at MGH where PET imaging for the study was performed, and Keith Johnson, MD, Professor of Neurology at HMS and the Gordon Center at MGH. Maeva Dhaynaut, PhD, contributed the study as part of her PhD training at the Gordon Center and the Pierre and Marie Curie Paris University in Paris (France). Giulia Sprugnoli, MD and neuroradiologist, participated in the study as part of her research fellowship at MGH and BIDMC.

illustration of the study design
Caption: Figure from the article illustrating the study design (credit: Dhaynaut, et al.)

The scientists tested the application of a novel noninvasive therapeutic approach to modulate brain oscillatory activity and promote clearance of toxic proteins that aggregate in the brain of patients with AD. Preclinical data in a mouse model of AD have shown how optogenetic or sensory stimulation might lead to an increase in fast brain oscillatory activity, a decrease in protein aggregates (amyloid-β and tau) and cognitive amelioration. The team led by Santarnecchi has been able to translate such findings directly to patients with AD, testing the safety and preliminary efficacy of an intervention based on transcranial alternating current stimulation (tACS), a safe and painless technique that delivers low intensity electrical fields into the brain via electrodes placed on the scalp. Daily tACS sessions were conducted in patients with mild-to-moderate AD for a month. Brain activity was recorded via electroencephalography (EEG) every day, while Positron Emission Tomography (PET) data were acquired before and after the treatment to look at protein levels in the brain. Results showed a significant increase in oscillatory activity in the gamma band targeted by tACS, and a preliminary effect on tau protein levels without any adverse effects.

Prof. Santarnecchi noted, “The results are preliminary, and we should avoid overinterpretation of the data. The observed effect suggests that tACS might be effective in boosting gamma oscillatory activity in the Alzheimer’s brain, and that this might be associated to increase clearance, mimicking what recently observed in a mouse model of AD from a team at the Massachusetts Institute of Technology (MIT). However, the small sample size limits our interpretations and demands replication, even though initial evidence of efficacy on protein clearance represents a positive sign in the right direction. We also recently documented a modulation of hippocampal blood flow in a larger sample of AD patients exposed to tACS, providing further support to the present findings. We are now running larger trials with funding from the National Institute of Health, hopefully we will be able to replicate the result in a larger sample and gain more insight on the mechanisms of action of tACS in AD.”

Patients received 1 hour of daily tACS for 1 month with an extensive nuclear imaging assessment (PET) at baseline and after the intervention to monitor for changes in protein load and microglia activity, along with electrophysiological and cognitive evaluation. The study was done on 4 patients with mild to moderate AD. Stimulation templates were developed to target the bilateral temporal lobes, the areas of the brain with highest levels of tau protein accumulation. Given the delicate patient population, the long and innovative intervention and the extensive assessment required before and after the treatment, which included up to 55 study visits per patient, the sample size was small, and the study was preliminary in nature. In parallel, Santarnecchi and his team has conducted other pilot trials with moderate samples where changes in gamma activity and brain blood flow were also observed.

“The technique still requires further testing to optimize stimulation parameters and fully personalize the treatment for each patient. Overall, tACS represents a potential new technology with a good safety profile and the possibility to be used in combination with almost any other therapy, thanks to its noninvasiveness and portability.” Santarnecchi continued.

Approximately 5.8 million people in the US live with Alzheimer’s disease – the sixth-leading cause of death in the country, according to the Alzheimer’s Association. It is estimated that 500,000 new cases of the disease are diagnosed in the US annually.


Full study
: “Impact of 40 Hz Transcranial Alternating Current Stimulation on Cerebral Tau Burden in Patients with Alzheimer’s Disease: A Case Series” by Maeva Dhaynaut, Giulia Sprugnoli, Davide Cappon, Joanna Macone, Justin S. Sanchez, Marc Normandin, Nicolas Guehl, Giacomo Koch, Rachel Paciorek, Ann Connor, Daniel Press, Keith Johnson, Alvaro Pascual-Leone, Georges El-Fakhri, and Emiliano Santarnecch (DOI: 10.3233/JAD-215072), published online in the Journal of Alzheimer’s Disease in advance of the publication of Volume 85, Issue 4. The article is available at:

The full text of the article is available to journalists from Diana Murray, IOS Press (, +1 7186405678). The media contact at Massachusetts General Hospital is Mike Morrison (, +1 6177246425).

About the Journal of Alzheimer’s Disease
Now in its 24th year of publication, the Journal of Alzheimer’s Disease (JAD) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment, and psychology of Alzheimer’s disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease, and clinical trial outcomes. JAD has a Journal Impact Factor of 3.909 according to Journal Citation Reports (Clarivate, 2020). The journal is published by IOS Press.

About IOS Press
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