Aftobetin-HCl and Fluorescence Detection Measured by Sapphire II to Determine the Number and Timing of Administrations

Open label study. 45-105 subjects will be enrolled.

Subjects will undergo the following procedures:

- Complete physical and neurologic examination (Screening)

- Neuropsychological testing (Screening)

- Ophthalmologic examination (Screening and Visit 4 (Safety follow up visit))

- Administration of ointment - 3 administrations (Visit 1)

- Sapphire II Fluorescent Eye Measurements (Visits 1-3): Prior to first administration of
ointment and then 24 +/- 2 hours, 28 +/- 30 minutes and 48 +/- 2 hours following first
ointment administration

- Amyvid Positron Emission Tomography (PET) Amyloid Scan (only required for MCI and mild
AD subjects who have not had a positive amyloid PET scan in the last 3 years)

Subjects will also be asked to participate in an elective second Sapphire II assessment to
assess its reproducibility. Repeatability testing is optional and will require a separate
consent. Subjects will come back for Visits 5-9 (ointment administration and eye scans and a
follow up safety assessment).

For MCI and mild AD subjects:

1. Aged 55-90 years old inclusive;

2. Able to provide informed consent;

3. Subject must have a reported memory concern verified by study partner (a study partner
is someone willing to participate as a source of information and has at least weekly
contact with the subject);

4. Capable of cooperating for the duration of the study with procedures and assessments;

5. Magnetic Resonance Imaging (MRI) Scan within 9 months with:

1. Modified Hachinski Score <4

2. No evidence of infection, infarction (ischemic or hemorrhagic), or other focal
lesions (tumors, subdural hematomas, malformations, etc.)

6. Geriatric Depression Scale (GDS) score of <6;

7. Neuropsychiatric Inventory (NPI) total score <10 and <4 in any NPI domain;

8. Sufficient vision in at least one eye and hearing to participate in cognitive testing

For MCI subjects:

9. Meets National Institute on Aging-Alzheimer's Association (NIA-AA) core clinical
criteria for Mild Cognitive Impairment due to AD1;

10. Clinical dementia Rating Scale Score (CDR) of 0.5 (memory box score must = 0.5);

11. Mini-Mental State Exam (MMSE) score of >24;

12. Abnormal memory function on education adjusted Wechsler Memory Scale Logical Memory II
subscale (Delayed Paragraph Recall, Paragraph A only) - Revised (16 years: <11; 8-15
years: <9; 0-7 years: <6);

13. Absence of dementia: no significant impairment in cognitive functioning or Activities
of Daily Living (AODLs) - Functional Assessment Questionaire (FAQ) score of <6. The
FAQ is answered by the study partner;

For Mild AD subjects:

14. Meets National Institute on Aging-Alzheimer's Association (NIA-AA) core clinical
criteria for probable AD dementia2;

15. CDR between 0.5 or 1;

16. MMSE score between 20 to 26 (inclusive);

17. Abnormal memory function on education adjusted Wechsler Memory Scale Logical Memory II
subscale -(Delayed Paragraph Recall, Paragraph A only) -Revised (16 years: <8; 8-15
years: <4; 0-7 years: <2);

18. Functional Assessment Questionaire (FAQ) score of >6. The FAQ is answered by the study
partner;

For CN subjects:

19. Subject must be free of memory complaints;

20. Cognitively normal, based on an absence of significant impairment in cognitive
functions or activities of daily living;

21. Normal memory function documented by scoring above education adjusted cut-offs on the
Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the
Wechsler Memory Scale - Revised (≥11 for 16 or more years of education; ≥9 for 8-15
years of education;

22. MMSE score of 29-30;

23. CDR Scale Score of 0;

24. Aged 25-40 years old inclusive; and

25. Negative family history for onset of memory dysfunction in first or second degree
relatives before age 65.

Exclusion Criteria:

1. Serious underlying medical disease which in the opinion of the investigator may
interfere with the participant's ability to participate in the study such as unstable
cardiac, pulmonary, renal, hepatic, endocrine, hematologic, active malignancy or
infectious disease;

2. Non-AD causes of dementia that could cause impaired memory ruled out by standardized
work up for dementia;

3. Significant neurologic disease (e.g., Parkinson's Disease, Huntington's disease,
normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure
disorder, subdural hematoma, multiple sclerosis);

4. Clinically relevant, abnormal serum chemistry, B12, TSH, and CBC <6 months of study
entry;

5. History of significant head trauma followed by persistent neurologic defaults or known
structural brain abnormalities, learning disability or mental retardation;

6. Significant psychiatric illness in last year such as major depression, bipolar,
obsessive compulsive or psychotic disorder;

7. History of alcohol or substance abuse in last year;

8. Pain or sleep disorder that could interfere with cognitive testing;

9. Known hypersensitivity to Amyvid (Florbetapir-F 18) or any components of injection
formulation or contraindication to PET scan (e.g., pregnant, lactating, or of
childbearing potential) in subjects requiring a PET scan.

10. Receiving any investigational medications or participated in a trial with
investigational medications within 30 days prior study entry;

11. History of bilateral cataract surgery;

12. Active ocular inflammation or infection;

13. History of physical injury or other serious eye disease;

14. Corneal disease that prevents visualization of the lens, e.g, Fuch's dystrophy or
keratokonus;

15. Inability to tolerate the PET environment, e.g., due to physical size and/or
claustrophobia in subjects requiring a PET scan.

16. Serious suicidal ideation in the opinion of the investigator or answers 'yes' to Item
4 or 5 on the Columbia Suicide Severity Rating Scale (CSSRS) at screening;

17. Inability to undergo MRI procedure (e.g., metal implant, metallic devices, e.g.,
non-MRI-safe cardiac pacemaker or neuro-stimulator, some artificial joints, metal
pins, surgical clips, other implanted metal, or claustrophobia or discomfort in
confined spaces)

18. May not be taking any of the following psychoactive medications:

- Regular use narcotic analgesics (>2 doses/ week)

- Clonidine, neuroleptics, antidepressants with central anticholinergic activity

- Other agents with central anticholinergic activity such as diphenhydramine,
hydroxyzine, benztropine

- Diazepam, clonazepam, temazepam, chlordiazepoxide, or triazolam

Note: it is permitted to remain on the following psychoactive medications provided the
subject has been receiving them for greater than or equal to 4 weeks:

- Antidepressants lacking significant anticholinergic side effects

- Estrogen replacement therapy

- Gingko biloba

- Sedative hypnotics: lorazepam, buspirone, oxazepam, zolpidem, zaleplon, alprazolam,
chloral hydrate

Note: it is permitted to remain on the following psychoactive medications provided the
subject has been receiving them for greater than or equal to 12 weeks:

- Cholinesterase inhibitors

- Memantine Note: the washout from psychoactive medication (e.g., excluded
antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics) must be at
least 4 weeks prior to screening.