tACS for Amyloid-β Reduction in Alzheimer's Disease

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. There is no current
treatments that alter disease progression.

Investigators will recruit 20 individuals with AD with evidence of amyloid placques in the
brain through Positron Emission Tomography (PET) imaging. Investigators will use a novel
approach, transcranial alternating current stimulation (tACS), to target the region of
maximum amyloid burden in the brain. All participants will receive tACS. Each individual's
participation in the study will consist of approximately 16 visits: 3 days for
screening/baseline procedures as described below, 10 tACS study visits, and 3 days for
follow-up assessments. Subjects will undergo baseline cognitive assessment, structural and
functional MRI characterization, and resting-state EEG measurement. Additionally, patients
will undergo a tACS-EEG recording session to assess brain plasticity levels and identify
markers of response to stimulation. All subjects will then undergo 10 1-hour sessions of
gamma-frequency (40 Hz) tACS, targeted to the region of maximal tracer uptake on the amyloid
PET study. Subjects will take a standardized adverse effect questionnaire before and after
each session and complete a short cognitive test after each session to demonstrate safety and
tolerability. At the end of the 10 sessions, subjects will then repeat the baseline
assessments, followed by repeat amyloid PET imaging to assess for changes in amyloid burden.

Investigators anticipate that targeting the region of amyloid burden in the brain with tACS
will reduce the amyloid burden as evidence by the follow up PET imaging and show improvement
on electrophysiological measures of brain function and on cognitive testing. If our
prediction is correct, this will will provide a critical first step in the development of a
novel intervention to prevent and treat AD.

Inclusion Criteria:

- Clinical Diagnosis of mild AD defined by: Clinical Dementia Rating (CDR) = 0.5-1, Mini
Mental State Examination (MMSE) >/= 20, Demonstration or history of memory impairments

- 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

- Intelligence Quotient (IQ) > 85 as determined by the Wechsler Test of Adult Reading
(WTAR) and 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, 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.

- Past or current history of major depression, bipolar disorder or psychotic disorders,
or any other major psychiatric condition.

- Contraindication for undergoing MRI or receiving Transcranial Magnetic Stimulation
(TMS) or tACS,

• 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, Transcutaneous Electrical 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 Central
Nervous System (CNS) active drugs.

- All female participants that are pre-menopausal will be required to have a pregnancy
test; any participant who is pregnant will not be enrolled in the study.

- BMI > 40 kg/m2. We will limit the BMI to <40 kg/m2 because of weight limits of the
scanner bed and width limits of the MRI.

- 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)