A 2-Part Randomized, Placebo-Controlled, Double-Blind, Single and Multiple Ascending Dose Study to Investigate Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of JNJ-63733657 in Healthy Subjects and Subjects With Alzheimer*s Disease

Each potential subject must satisfy all of the following criteria to be enrolled in the study: ;1. Male or female. Note: equal gender representation is preferred when feasible. ;2. 55 to 75 years of age, inclusive.;3.1. body mass index (BMI) between 18 and 35 kg/m2, inclusive (BMI = weight/height2) and
body weight greater than 40 kg but less than 110 kg at screening.;4.1 otherwise healthy for their age group (Part 1 and Part 2-HS) or medically stable (Part 2 AD) on the basis of physical examination, medical history, vital signs, and 12 lead ECG performed at screening or admission to the clinical unit. If there are abnormalities, they must be consistent with the underlying illness or age of the study population and not deemed clinically unstable. This determination must be recorded in the subject's source documents and initialed by the investigator;5. 1 otherwise healthy for their age group (Part 1 and Part 2-HS) or medically stable (Part 2 AD) on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel (including liver enzymes), hematology, coagulation or urinalysis are outside the normal reference ranges, the subject may be included only if the investigator judges the abnormalities to be not clinically significant. This determination must be recorded in the subject's source documents and initialed by the investigator.

6. Women must not be of childbearing potential defined as: ;• Postmenopausal: A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level at screening (>40 international units per liter (IU/L) or milli-international units per milliliter [mIU/mL]) in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy, however in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.;• Permanently sterile: Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures, and bilateral oophorectomy.;Note: If reproductive status is questionable, additional evaluation will be considered;7. During the study and up to 16 weeks after receiving the last dose of study drug a man:;• who is sexually active with a woman of childbearing potential and has not had vasectomy must agree to use a barrier method of contraception (e.g., condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository). In addition, their female partner should also use a highly effective method of birth control (e.g. hormonal contraception) for at least the same duration.;• who is sexually active with a woman who is pregnant must use a condom. ;• must agree not to donate sperm.;8. must be willing to adhere to the prohibitions and restrictions specified in this protocol.;9. must sign an informed consent form (ICF) (or their legally acceptable representative;depending on disease state) indicating that he or she understands the purpose of, and;procedures required for, the study and is willing to participate in the study.;4.1.2 Specific Inclusion Criteria Part 2;Each potential subject enrolled in Part 2-AD must satisfy all of the following specific criteria in addition to the general criteria to be enrolled in the study:;10. Clinical Dementia Rating (CDR) global rating score of 0.5 or 1.0 at screening.;11. must have a reliable informant (e.g., relative, partner, friend).;12. must have CSF finding consistent with AD pathology: abnormal CSF A-β 1-42 levels and elevated CSF p-tau181P or t-tau levels at screening#.;Note: #cut off value for CSF ratio A-β1-42, t-tau and p-tau181P will be based on the value established by the central CSF screening lab and specified in a separate lab manual.;13. 55 to 80 years of age, inclusive
-AD
4.1.3. Specific Inclusion Criteria Part 2-HS
Each potential subject enrolled in Part 2-HS must satisfy all of the following specific criteria in addition to the general criteria to be enrolled in the study:;14. 55 to 80 years of age, inclusive

Any potential subject who meets any of the following criteria will be excluded from participating in the study:;1.1 history of or current liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic (including but not limited to neurodegenerative disease (excluding AD for Part 2-AD) [e.g., Parkinson*s disease], seizure disorders, transient ischemic attacks, etc.), hematologic (including coagulation disorders), rheumatologic, psychiatric, or metabolic disturbances, any inflammatory illness or any other illness that the Investigator considers should exclude the subject.
2.1 relevant history of or current neurological disease (other than prodromal AD or mild AD for Part 2-AD), which in the opinion of the investigator may make interpretation of possible new neurological signs or symptoms difficult
3.1. Positive result on hepatitis B surface antigen (HBsAg), hepatitis B core antibody
(HBcAb), hepatitis C antibody (anti-HCV), or any other clinically active liver disease at
screening (per screening evaluations)
4. History of human immunodeficiency virus (HIV) antibody positive, or tests positive for HIV at Screening (per screening evaluations)
5. Any contra-indications for magnetic resonance imaging (MRI) (prostheses, implants, claustrophobia, pacemakers, etc)
6. Evidence of any brain disease other than potential very early signs of AD (e.g., mild hippocampal atrophy) or typical age-related changes (e.g., mild white matter hyperintensity on MRI), that could explain the cognitive deficit (including, but not limited to vascular encephalopathy or strokes, as imaged by cerebral MRI and Major Depression, as defined by DSM (current edition) criteria. The screening MRI scan shall be interpreted by a local radiologist and investigator for exclusionary findings prior to enrolling the subject.
7. history of malignancy within 5 years before screening (exceptions are squamous and
basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that
in the opinion of the investigator, with written concurrence with the sponsor's medical
monitor, is considered cured with minimal risk of recurrence).
8. history of drug or alcohol use disorder according to DSM (latest edition) criteria within
6 months before Screening or has a positive test result(s) for alcohol and/or drugs of
abuse (including: opiates (including methadone), cocaine, amphetamines,
methamphetamines, cannabinoids, barbiturates, and benzodiazepines) at screening or
admission to the clinical unit.
9.1. drinks, on average, more than 8 cups of tea/coffee/cocoa/cola/caffeinated beverages
(e.g., energy drink) per day for Part 1 subjects.
10. clinically significant acute illness within 7 days prior to study drug administration.
11.1. smokes cigarettes (or equivalent) and/or has used nicotine based products within 3 months prior to study drug administration for Part 1 subjects.
12. man who plans to father a child while enrolled in this study or within 13 weeks after the
last dose of study drug.
13. history of clinically significant drug and/or food allergies.
14. known or suspected intolerance or hypersensitivity to any biologic medication or
known allergies or clinically significant reactions to human proteins, monoclonal
antibodies or antibody fragments, or any of the excipients of JNJ-63733657 (refer to
Investigator's Brochure).2
15. taken any disallowed therapies as noted in Section 8, Prestudy and Concomitant
Therapy before the planned first dose of study drug. The use of medication that is
considered not to have any impact on the study results may be allowed after agreement
between the investigator and the sponsor's medical monitor.
Note: Medication for chronic use except for those medications specifically listed in
Section 8, Prestudy and Concomitant Therapy will be allowed after approval by both
the investigator and the sponsor's medical monitor. This medication should be kept
stable from the screening visit until completion of the double-blind treatment phase.
16. received an investigational drug (including vaccines) or used an investigational medical
device within 3 months or 5x T1/2, whichever is longest before the planned start of study
or are currently enrolled in an investigational study.
17. previously participated in a tau vaccine or tau/amyloid antibody study.
18. had major surgery, (e.g., requiring general anesthesia) within 8 weeks before screening,
or will not have fully recovered from surgery, or has surgery planned during the time
the subject is expected to participate in the study or within 3 months (>=5 half-lives) after
study drug administration.
Note: subjects with planned surgical procedures to be conducted under local anesthesia
may participate.
19. donated one or more units (approximately 450 mL) of blood or acute loss of an
equivalent amount of blood within 90 days prior to study drug administration.
20. relevant history of lower back pain or scoliosis and/or major (lumbar) back surgery
(microdiscectomy is allowed) that could impact the ability to have a LP in the opinion
of the investigator.
21. topical infection or local dermatological condition at the puncture site prior to puncture
(screening), that may compromise the LP.
22. signs of increased intracranial pressure, e.g., based on clinical or MRI examination.
23. any condition for which, in the opinion of the investigator, participation would not be in
the best interest of the subject (e.g., compromise the well-being) or that could prevent,
limit, or confound the protocol-specified assessments.
24. employee of the investigator or study site, with direct involvement in the proposed
study or other studies under the direction of that investigator or study site, as well as
family members of the employees or the investigator.
25. vulnerable subjects (e.g., a person kept in detention or a person under guardianship).
NOTE: Section 17.4, Source Documentation, describes the required documentation to support
meeting the enrollment criteria.
4.2.2. Specific Exclusion Criteria Part 1and Part 2-HS
26. MMSE score <=27 at screening.
4.2.3. Specific Exclusion Criteria Part 2-AD
27. evidence of brain disease, other than AD, that could explain the cognitive deficit
(including, but not limited to, vascular encephalopathy or strokes, as imaged by
cerebral MRI).