Gamma Induction for Amyloid Clearance in Alzheimer's Disease

  • End date
    Nov 23, 2023
  • participants needed
  • sponsor
    Massachusetts General Hospital
Updated on 23 October 2022
positron emission tomography
mini-mental state examination
alzheimer's disease
mental state examination
cholinesterase inhibitors
memory impairment
senile plaques
brain stimulation
memory loss


Alzheimer's Disease (AD) is characterized by amyloid-β (Aβ) plaque buildup and phosphorylated tau (p-tau) in the brain, as well as widespread neurodegeneration. Amyloid-β and tau are proteins that build up in the brain that may contribute to memory problems. The evidence suggests that both amyloid and tau play a critical role in AD and interventions that reliably and safely decrease the intracerebral burden of amyloid or tau could potentially be of marked clinical importance. Currently, therapeutic options are very limited and while there are pharmacologic interventions that transiently improve cognitive function, there are no treatments that alter disease progression.

The purpose of this study is to see if multiple daily sessions of non-invasive brain stimulation can affect brain activity to decrease the amount of amyloid and tau in people with AD as compared to Sham (placebo) stimulation. The type of brain stimulation that will be used is called transcranial alternating current stimulation (tACS). This study will investigate different doses of tACS (2-4 weeks) and assess safety. The hope is that tACS will decrease the amount of amyloid and tau and improve memory and thinking in people with AD.


This is an interventional, sham controlled, double-blind study in patients with early to moderate Alzheimer's Disease (AD). The study will enroll approximately 55 individuals with amyloid positive Mild Cognitive Impairment (MCI) or AD. Each subject will undergo a 1-2 visit screening period consisting of a physical and neurological exam, medical history and medication review, safety questionnaires, and cognitive testing. Each subject will then undergo 5-7 baseline visits including neuropsychological testing (memory and thinking tests), amyloid Positron Emission Tomography (PET) imaging if one is not available or it has been greater than 6 months, tau PET imaging, tACS-EEG (transcranial alternating current stimulation and electroencephalogram) assessment, TMS-EEG (transcranial magnetic stimulation and electroencephalogram) plasticity assessment, functional magnetic resonance imaging (fMRI), blood and saliva sample collection, and optional lumbar puncture (LP). Participants will be randomly assigned to one of four groups: stimulation for 2 weeks or 4 weeks, once a day or twice a day. One of the groups is a sham group. This means that this group will not receive actual tACS. Each session will be one hour of either individualized gamma-frequency (40 Hz) tACS or sham tACS, depending on the assigned group. Subjects will be assessed for any side effects before and after each session and complete a short memory and thinking test either daily or weekly. At the end of the daily sessions, 5-7 follow up visits will include a repeat of the baseline measures including amyloid and tau PET scans. Long-term follow-up visits will include an EEG, cognitive testing and an amyloid PET scan. The PET imaging studies will be conducted at Massachusetts General Hospital and up to 5 PET scans will be performed.

Condition Alzheimer Disease, Mild Cognitive Impairment
Treatment Transcranial Alternating Current Stimulation (tACS), Sham Transcranial Alternating Current Stimulation
Clinical Study IdentifierNCT03880240
SponsorMassachusetts General Hospital
Last Modified on23 October 2022


Yes No Not Sure

Inclusion Criteria

Clinical Diagnosis of early to moderate AD
Mini Mental State Examination (MMSE) ≥ 18
Clinical Dementia Rating (CDR) ≥ 0.5
Demonstration or history of memory impairments
Confirmation of diagnosis will be made by the study MD based on a holistic consideration of the participant's cognitive evaluation and history
Amyloid positive PET imaging
At least 45 years old
On a stable dose of medications for memory loss including cholinesterase inhibitors (e.g. donepezil, rivastigmine or memantine) as defined as 6 consecutive weeks of treatment at an unchanging dose
Minimum of completed 8th grade education
No history of intellectual disability

Exclusion Criteria

Current history of poorly controlled migraines including chronic medication for migraine prevention
Current or past history of any neurological disorder other than dementia, such as epilepsy, stroke (cortical stroke), progressive neurologic disease (e.g. multiple sclerosis) or intracranial brain lesions; and history of previous neurosurgery or head trauma that resulted in residual neurologic impairment
Non-cortical disease such as confluence white matter changes (including lacunar infarcts < 1cm) and asymptomatic, subacute, cerebellar infarcts may be included upon review of a medically responsible neurologist
Past or current history of major depression, bipolar disorder or psychotic disorders
or any other major psychiatric condition
Contraindication for undergoing MRI or receiving TMS or tACS
>50 mSv of radiation exposure for research within the past year (PET imaging exclusion)
History of fainting spells of unknown or undetermined etiology that might constitute seizures
History of seizures, diagnosis of epilepsy, history of abnormal (epileptiform) EEG or immediate (1st degree relative) family history of epilepsy; with the exception of a single seizure of benign etiology (e.g. febrile seizure) in the judgment of the investigator
Chronic (particularly) uncontrolled medical conditions that may cause a medical emergency in case of a provoked seizure (cardiac malformation, cardiac dysrhythmia, asthma, etc.)
Metal implants (excluding dental fillings) or devices such as pacemaker, medication pump, nerve stimulator, TENS unit, ventriculo-peritoneal shunt, cochlear implant, unless cleared by the study MD
Substance abuse or dependence within the past six months
Medications will be reviewed by the responsible MD and a decision about inclusion will be made based on the following: The patient's past medical history, drug dose, history of recent medication changes or duration of treatment, and combination of CNS active drugs
All female participants that are pre-menopausal will be required to have a pregnancy test; any participant who is pregnant or breastfeeding will not be enrolled in the study
Subjects who, in the investigator's opinion, might not be suitable for the study
A hair style or head dress that prevents electrode contact with the scalp or would interfere with the stimulation (for example: thick braids, hair weave, afro, wig)
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