Dose-Finding Study To Evaluate the Safety and Tolerability of E2609 in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal Alzheimer's Disease) and Mild to Moderate Dementia Due to Alzheimer's Disease

Inclusion criteria:

Participants must meet all of the following criteria to be included in the Core Study
(Prerandomization and Randomization Phases):

1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD (which is
consistent with Prodromal AD) or AD dementia and is 'staged' or classified as either
MCI or mild to moderate dementia.

2. Amyloid positive Positron Emission Tomography (PET) image based on centralized PET
scan reading.

3. Male or female, age 50 to 85 years, inclusive at time of consent.

4. Must have an identified caregiver or informant who is willing and able to provide
follow-up information on the participant throughout the course of the study.

5. If receiving an Acetylcholinesterase Inhibitor (AChEI) or memantine, must have been on
a stable dose for at least 12 weeks before the Baseline cognitive assessments, with no
plans for dose adjustment in the foreseeable future. Treatment-naive participants can
be entered into the study but there should be no plans to initiate treatment with
AChEIs or memantine at the time of entry into the study.

6. Must have been on stable doses of all other permitted chronically used concomitant
medications (ie, not related to their cognitive decline) for at least 4 weeks before
randomization.

Participants must meet all of the following criteria to be included in the Open-Label
Extension (OLE) Phase of the study:

1. Participants who complete the 18-month treatment and the 12-week follow-up period
(Visit 20) in the Core Study and whose Visit 20 falls within a 4-week window from the
start of the OLE Phase (Visit 21). Permission must be obtained from the Medical
Monitor if the Visit 21 is to occur more than 4 weeks from Visit 20.

2. Participants must continue to have an identified caregiver or informant who is willing
and able to provide follow-up information on the participant throughout the course of
the OLE Phase.

Exclusion criteria:

Participants who meet any of the following criteria will be excluded from the Core Study:

1. Any neurological condition that may be contributing to cognitive impairment above and
beyond that caused by the participant's AD pathology, including any co-morbidities
such as cerebrovascular disease, detected by medical history, neurological
examination, or magnetic resonance imaging (MRI).

2. History of transient ischemic attacks or stroke within 12 months of Screening.

3. History of epilepsy.

4. Evidence of depression on a rating scale at Screening or any psychiatric diagnosis or
symptoms, (eg, hallucinations, major depression, etc.) that could confound the
diagnosis or could interfere with study assessments or procedures. This includes
suicidal ideation or suicidal behavior within 6 months prior to Screening, or
hospitalization or treatment for suicidal behavior in the past 5 years.

5. Abnormally low serum vitamin B12.

6. Thyroid stimulating hormone above the normal range. This applies to all participants
regardless of whether or not they are taking thyroid supplements.

7. Participants with liver disease (hepatic impairment), at Screening or Baseline.
Participants with Gilbert's syndrome need not be excluded.

8. Not able to have a MRI, PET scanning, or CSF collection by Lumbar Puncture (LP)
(applicable to participants consenting to CSF sample collection).

9. Severe visual or hearing impairment that would prevent the participant from performing
psychometric tests accurately.

10. History of immunodeficiency disorders.

11. Participants with chronic viral hepatitis.

12. History of Tuberculosis (TB). Participants with no history of TB will be tested for
previous TB exposure and a positive test will be exclusionary.

13. History of ophthalmic shingles or ocular Herpes Simplex Virus (HSV) infection.

14. Any live vaccine in the 3 months or any active infection within the last 4 weeks
before study drug administration (i.e. randomization).

15. Any chronic inflammatory disease that is not adequately controlled or requires
immunosuppressive or immunomodulatory therapy.

16. T helper cell, cytotoxic T cell, or B cell absolute counts below normal.

17. Immunoglobulin (Ig) IgG, IgA, or IgM levels below normal at Screening or Baseline,
unless both the Investigator and the Medical Monitor agree that the finding is not
clinically significant.

18. Clinically significant deviation from normal in physical examination, vital signs, or
clinical laboratory tests at Screening or Baseline.

19. Exclusionary cardiac factors include: prolonged QT interval greater than 450
milliseconds (msec) from electrocardiograms (ECGs); history of risk factors for
torsade de pointes or the use of concomitant medications that prolong the QT/QTc
interval; left bundle branch block; persistent low or high heart rate; persistent low
or high blood pressure; history of cardiac arrhythmias; other clinically significant
ECG abnormalities.

20. Type 1 or Type 2 diabetes mellitus that is not well controlled.

21. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell
carcinoma in situ of the skin, or localized prostate cancer that did not require
systemic therapy; these do not exclude the participant).

22. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that
are not stably controlled, or which, in the opinion of the investigator(s), could
affect the participant's safety or interfere with the study assessments.

23. Hypopigmentation conditions (eg, albinism and vitiligo).

24. Known or suspected history of drug or alcohol dependency or abuse within 2 years,
current use of recreational drugs or a positive urine drug test.

25. Planned surgery that requires general, spinal, or epidural anesthesia that would take
place during the study.

26. Participation in any other interventional clinical study related to cognitive
impairment within 6 months before Screening unless it can be documented that the
participant was in a placebo treatment arm.

27. Currently enrolled in another clinical study or used any investigational drug or
device within 60 days or 5 half-lives of the investigational medication (whichever is
longer) proceeding informed consent.

28. Hypersensitivity to the study drug or any of the excipients or to other Beta Secretase
Cleaving Enzyme (BACE) inhibitors, or to the PET tracer, or components of its
formulation.

29. Females who are lactating or pregnant. Females of childbearing potential who do not
agree to adhere to the protocol specified methods for avoiding pregnancy.

30. Males who do not meet the protocol requirements for avoiding their partners becoming
pregnant. Sperm donation is not permitted.

Participants who meet any of the following criteria will be excluded from the OLE Phase of
the study:

1. Participants who discontinue study drug prematurely during the Core Study are not
eligible to participate in the OLE Phase.

2. Participants with any active infection within 4 weeks of Visit 21

3. Participants with absolute lymphocyte count below the lower limit of normal (LLN)
within 10 days of Visit 21

4. Participants who develop the following conditions from the time of screening for the
Core Study to the start of the OLE Phase:

1. Hepatic impairment, with total bilirubin greater than 1.5 × the upper limit of
normal (ULN) or International Normalized Ratio (INR) greater than 1.7.
Participants with Gilbert's syndrome need not be excluded on the basis of an
elevated bilirubin, provided that they have no other signs or symptoms suggestive
of hepatic impairment.

2. Any contraindications to MRI scanning, including cardiac pacemaker/defibrillator
or ferromagnetic metal implants (eg, in skull; cardiac devices other than those
approved as safe for use in MRI scanners)

3. Severe visual or hearing impairment that would prevent the participant from
performing psychometric tests accurately

4. Immunoglobulin (Ig) deficiency or other immunodeficiency disorders

5. Chronic viral hepatitis

6. Tuberculosis

7. Ophthalmic shingles

8. Ocular herpes simplex virus (HSV) infection

9. Any chronic inflammatory disease that is not adequately controlled or that
requires systemic or ocular immunosuppressive or immunomodulatory therapy.
Participants with:

- Seasonal or perennial allergic rhinitis, asthma or chronic obstructive
pulmonary disease where the condition is considered to be stable and
adequately controlled by inhaled steroids need not be excluded

- Hashimoto's thyroiditis but who are stable on thyroid replacement therapy
and not on systemic immunosuppressive therapy need not be excluded

- Cutaneous manifestations of immunological disease that do not require
systemic immunosuppressive therapy or systemic immunomodulatory therapy need
not be excluded (topical steroid treatment is permitted)

10. Malignant neoplasms (except for basal or squamous cell carcinoma in situ of the
skin, or localized prostate cancer that did not require systemic therapy; these
do not exclude the subject from OLE).

5. Participants with prolonged QT interval corrected by the Fridericia correction formula
(QTcF) at Visit 20 or Visit 21. Participants with a single 12-lead ECG QTcF >450 msec
should have 2 additional ECGs performed at least 1 minute apart and the mean QTcF from
the triplicate ECGs should be calculated. Participants with a mean QTcF value >450
msec are not eligible to enter the OLE Phase.

6. Participants with significant pathological findings on brain MRI including but not
limited to: an area of superficial siderosis; evidence of cerebral vasogenic edema;
evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations,
or infective lesions; evidence of multiple lacunar infarcts or stroke involving a
major vascular territory, severe small vessel, or white matter disease; space
occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or
arachnoid cysts and less than 1 centimeter at their greatest diameter need not be
exclusionary).

7. Participants who have a "yes" answer to the Columbia Suicide Severity Rating Scale
(C-SSRS) suicidal ideation questions 4 or 5 at Visit 20 or Visit 21 or any suicidal
behavior during the study prior to the start of the OLE Phase.

8. Females who are lactating or pregnant. Females of childbearing potential who do not
agree to adhere to the protocol specified methods for avoiding pregnancy.

9. Participants with medical conditions (eg, cardiac, respiratory, gastrointestinal,
renal disease) that are not stably controlled, or which, in the opinion of the
investigator(s), could affect the participant's safety or interfere with the study
assessments.

10. Any other clinically significant abnormal findings in vital signs, ECGs and laboratory
tests that would, in the investigator's opinion, affect the particiapant's safety or
interfere with study assessments during the OLE Phase