Stimulating Neural Activity to Improve Blood Flow and Reduce Amyloid: Path to Clinical Trials

Alzheimer's Disease (AD) is a looming epidemic, with an urgent need for new therapies to
delay or prevent symptom onset and progression. There is growing awareness that clinical
trials must target stage-appropriate pathophysiological mechanisms to effectively develop
disease-modifying treatments. Advances in AD biomarker research have demonstrated changes in
amyloid, brain metabolism, and other pathophysiologies prior to the onset of memory loss,
with some markers possibly changing one or two decades earlier. The brain region responsible
for spatial navigation and memories of experience, the hippocampus, is one of the areas first
affected in Alzheimer's disease (AD) and other memory disorders. Prior research has shown how
coordinated electrical activity across many neurons in the hippocampus represents memories of
experiences and this coordinated activity fails in animal models of AD. The research also
showed that stimulating neurons to produce a specific component of this activity, called
gamma oscillations, reduces AD pathology. The goal of this proposal is to translate this
discovery that stimulating specific patterns of neural activity is neuroprotective from
rodents to humans using a non-invasive approach. This research includes preclinical testing
that will be used to design and justify a multi-site clinical trial to test this approach as
a treatment for AD, for which there are currently no effective therapies.

Cognito Therapeutics has licensed the technology from prior animal research to transition
this work to humans. The company will provide the Flicker devices for conducting this study.
The device is similar to sunglasses and is both comfortable and easy to use.

Ten participants with mild cognitive impairment will be randomly assigned to two study arms.
Although all participants will receive Flicker exposure, half of the participants will
receive the exposure during the entire intervention period (8 weeks of Flicker) while the
other half of the participants will receive Flicker exposure only during the second half of
the intervention period (for 4 weeks of active treatment). During the course of the study,
participants will undergo venous blood draws and lumbar puncture for biomarker analyses at
baseline, midpoint and at the end of the intervention.

Inclusion Criteria:

- Subjects must have a subjective memory concern as reported by subject, study partner
or clinician.

- Meets local criteria for diagnosis of mild cognitive impairment (MCI).

- Montreal Cognitive Assessment (MoCA) score >15. Exceptions may be made for subjects
with less than 8 years of education at the discretion of the PI.

- Clinical Dementia Rating = 0.5. Memory Box score must be at least 0.5.

- General cognition and functional performance sufficiently preserved such that a
diagnosis of Alzheimer's Disease (AD) cannot be made by the physician at the time of
the screening visit.

- Stable on medications for 4 weeks prior to initiation of study sessions.

- Geriatric Depression Scale (GDS) ≤ than 6.

- Male or female outpatients aged 50-90 (inclusive).

- Able to hear without the use of hearing aids.

- Study partner who lives with the participant and can provide a reliable assessment of
the participant's level of function, is available for all clinic visits, and can serve
as a supervisor/monitor for the home-based Flicker sessions for the duration of the
study.

- Visual and auditory acuity adequate for neuropsychological testing.

- Good general health with no diseases expected to interfere with the study.

- Completed six grades of education or has a good work history (sufficient to exclude
mental retardation).

- Able to communicate in English with study personnel.

- Able to understand the nature of the study and provision of written informed consent
prior to conduct of any study procedures.

- Willing to undergo repeated magnetic resonance imaging (MRI) and positron emission
tomography (PET) scans.

- Agrees to blood collection for apolipoprotein E (ApoE) and biomarker testing.

- Agrees to lumbar puncture over the course of the study for the collection of
cerebrospinal fluid (CSF).

Exclusion Criteria:

- Any significant neurologic disease other than MCI and suspected incipient AD, such as
Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure
hydrocephalus, brain tumor, progressive supranuclear palsy, poorly controlled seizure
disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma
followed by persistent neurologic deficits or known structural brain abnormalities.

- Screening/baseline MRI scan with evidence of infection, large vessel infarction or
other focal structural lesions that could account for the memory deficits. Subjects
with multiple lacunes or lacunes in a critical memory structure are excluded.

- Contraindication to MRI due to pacemakers, aneurysm clips, artificial heart valves,
ear implants, metal fragments or foreign objects in the eyes, skin or body, or
excessive weight.

- Presence of clinically significant suicide risk, based on the Investigator's judgment
informed by a structured clinician interview. Any suicide attempt within the past 1
year of the screening visit is exclusionary.

- Major depression, bipolar disorder as described in Diagnostic and Statistical Manual
of Mental Disorders-4 (DSM-IV) within the past 1 year, or history of schizophrenia.

- Psychotic features, agitation or behavioral problems within the last 3 months which
could lead to difficulty complying with the protocol.

- History of alcohol or substance abuse or dependence within the past 2 years (DSM-IV
criteria).

- Known history of epilepsy or migraines, which may be exacerbated by study
intervention.

- History of narrow angle (acute angle) glaucoma.

- Current use of warfarin or other blood thinners (exclusionary for lumbar puncture).

- Inability to obtain initial CSF sample.

- Current use of Namenda (memantine).

- Current use of medications that lower seizure threshold, including Wellbutrin,
Ciprofloxacin, Levofloxacin, Seroquel, Phenergan, and Sumatriptan.

- Current use of anti-psychotic medication.

- CSF profile inconsistent with underlying Alzheimer's Disease pathology.

- Reasonable likelihood for non-compliance with the protocol or any other reason, in the
opinion of the investigator, prohibits enrollment of subject into the study.

- Exceptions to these guidelines may be considered on a case-by-case basis at the
discretion of the protocol director.