Gamma Induction for Alzheimer's Disease

This is an interventional, sham controlled, double-blind study in patients with mild to
moderate Alzheimer's Disease (AD). The study will enroll approximately 55 individuals with
amyloid positive 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:
2 weeks of daily tACS sessions, 4 weeks of daily tACS sessions, 4 weeks of twice daily tACS
sessions, or Sham (placebo) tACS sessions. 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. Participants without a significant reduction in amyloid on the follow-up amyloid PET
will undergo a repeat scan in 4 weeks. Participants with a significant reduction in amyloid
on the follow-up amyloid PET will be randomly assigned to a repeat scan at either 2, 4 or 8
weeks after the last scan. The PET imaging studies will be conducted at Massachusetts General
Hospital.

Inclusion Criteria:

- Clinical Diagnosis of mild 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)