Effect of Modulating Gamma Oscillations Using tACS

This study will leverage all this accumulated knowledge by implementing an intervention based
on multiple, individualized multifocal tACS stimulation sessions based on individual PET and
MRI information in patients with amyloid-positive PET with the hope that this leads to
microglia activation and decrease in cerebral amyloid and tau depositions in human patients
with AD.This would have immense translational impact, as gamma tACS is an intervention that
is portable, does not require expensive hardware, can be widely applied to large numbers of
patients with AD, as well as, given its favorable side effect profile, even to patients at
earlier stages of the disease who have cerebral amyloid/tau without clinical symptoms.

The investigators aim to enroll 10 individuals with AD with evidence of increased cerebral
amyloid burden on amyloid PET imaging. This would allow for a final sample size of 5-6 fully
evaluable subjects. Each subject's participation in this study will consist of approximately
31-35 visits: 1 day for consent and screening procedures, 5-7 days of baseline procedures
(this includes the PET scans), 20 tACS study visits, and 5-7 days of follow-up assessments.
Subjects will undergo baseline cognitive assessment, structural and functional MRI
characterization, PET imaging to assess amyloid burden, tau deposition and level of microglia
activation, and resting-state EEG measurement. Additionally, subjects will undergo a TMS-EEG
and a tACS-EEG recording session to assess brain plasticity levels and identify markers of
response to stimulation. All subjects will subsequently undergo 20 sessions of
gamma-frequency (40 Hz) tACS. At the end of the 20 sessions, subjects will then repeat the
baseline assessments over 5-7 visits, including repeat PET imaging to assess for changes in
amyloid burden, tau deposition, and microglia activation.

Inclusion Criteria:

- Clinical Diagnosis of mild to moderate AD*

- Mini Mental State Examination (MMSE) > 18

- Mild AD ≥ 21

- Moderate AD 18-20

- 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

- IQ> 85 as determined by the 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 TMS or tACS,

- >50 mSv of radiation exposure for research within the past year (PET imaging
exclusion)

- Presence of the Thr/Thr polymorphism in the TSPO gene (rs6971) due to low affinity
binding for the PBR 28 (microlgia) PET scan

- 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)