• Phase 1A SAD: Five or more cohorts of 8 healthy volunteers (HVs) will receive a single IV bolus injection of study drug or placebo. The first 4 cohorts will be male only. The last cohort will be repeated with the max safe dose of the previous cohorts in healthy elderly subjects (male and female of non childbearing potential, > 50years)
• Phase 1B MAD: Two or more cohorts of 8 male and female HVs will receive multiple (4) IV bolus injections of study drug or placebo every 72 hours.
• Phase 1 Subcutaneous SC Cohort: One cohort of 6 male and 6 female HVs will receive one SC injection of study drug.

This is a randomized, double-blind, placebo-controlled study in HV and in APOE4 carriers.

Phase 1A Single Ascending Dose (SAD): In 5 or more sequential SAD cohorts of 8 (6 active:2 placebo) HVs a single IV bolus injection (CS6253 1, 2.4, 6, and 10 mg/kg or placebo) will be administered and PK, safety, and biomarkers will be assessed. The first 4 cohorts will include males only. In the fifth cohort 8 (6 active:2 placebo) subjects, male and female of non-childbearing potential and at least 50 years old, will be administered CS6253 at equal to or lower doses than the maximum safe SAD dose in HV.

CSF will not be collected in the first 2 SAD cohorts. In the following cohorts, CSF will be collected before dosing and over 24 hours after dosing. Additional cohorts may be added as needed and deemed safe and appropriate by the Data Safety Monitoring Board (DSMB).

Phase 1B Multiple Ascending Dose (MAD): In 2 or more sequential MAD cohorts of 8 (6 active:2 placebo) male and female HVs at least 50 years old on average ≥ 3/sex/cohort; ≥ 4 APOE4 carriers/cohort, will be administered multiple IV bolus injections. Cohort 1 will be administered CS6253 at 75% of the maximum safe SAD dose in subjects at least 50 years old or placebo, and if no Treatment Emerging Adverse Events (TEAEs), in Cohort 2 at 100% of the maximum safe SAD dose or placebo will be administered every 72 hours x 4 doses and PK, safety, and biomarkers will be assessed. Plasma PK will be assessed after first and fourth dose in all cohorts. CSF will be collected before dosing and over 24 hours in conjunction with the fourth dose. Cohorts of 8 subjects (6 active:2 placebo) may be added at doses equal to or lower than the maximum safe MAD dose to further explore CS6253 brain exposure and Pharmacodynamics (PD) dependency on APOE4 isoform and sex.

Phase 1 Subcutaneous SC Cohort: One cohort of 6 (>=4) male and 6 (>=4) female HVs will receive one SC injection of study drug. From these 12 subjects (>=4) female and (>=4) male subjects need to be an APOE4 carrier.

Inclusion Criteria:

1. Male HVs at least 18 years old.

2. a) Cohort 5 only: Male and female HVs at least 50 years old and if female be of non-childbearing potential, i.e. meet at least one of the following criteria: postsurgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or postmenopausal (amenorrheic for at least 2 years and a serum follicle-stimulating hormone (FSH) > 30 IU/L).

   b) If subject is male, must be willing to use acceptable contraception from Day 1 until 30 days after the last dose of study drug.

3. The subject has a body mass index (BMI) within 18-32 kg/m² (inclusive).

4. The subject is in reasonably good health as determined by medical history and physical examination and clinical laboratory tests.

5. The subject is willing and able to speak, read, and understand Spanish and give signed informed consent.

6. The subject must agree to comply with a lumbar catheterization and collection of blood and CSF samples (SAD Cohorts 3-5 only and MAD cohorts).

7. The subject is willing and able to comply with all testing and requirements defined in the protocol.

8. The subject is willing, deemed compliant, and able to remain at the Clinical Research Unit (CRU) for the duration of the confinement period and return for all outpatient visits.

Phase 1B MAD

The eligibility criteria for the Phase 1B MAD study are the same as described for Phase 1A SAD, with the following exceptions:

1. At least 50 years old and female need to be of non-childbearing potential
2. Known to have at least 1 APOE4 allele (homozygous or heterozygous). Note: this criterion applies to on average for the MAD at least 4 APOE4 subjects per cohort.

Exclusion Criteria:

Subjects who meet any of the following criteria will not be enrolled:

1. The subject has any clinically significant deviations from normal in physical examination, ECG, or clinical laboratory tests, as determined by the investigator.
2. The subject has an increased bleeding risk or is treated with anti-coagulation therapies including but not limited to aspirin, coumarin, warfarin and heparin.
3. The subject has had a clinically significant illness within 30 days of check-in, as determined by the investigator.
4. The subject has a history of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, or metabolic disease.
5. History of Type 2 diabetes mellitus or hemoglobin A1c (HbA1c) > 7%.
6. Fasting triglycerides > 400 mg/dL
7. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (Cockcroft-Gault formula)
8. The subject has changed the frequency or dose of chronic medication within the last 8 weeks.
9. The subject has a history of substance abuse or a positive alcohol or urine drug screen at screening or at check-in.
10. The subject has a positive serum hepatitis B surface antigen or positive anti-hepatitis C virus test at the Screening Visit.
11. Have positive test results for, or evidence of active infection with, human immunodeficiency virus type 1 or 2, or hepatitis B, or C.
12. The subject has received an investigational drug within 30 days of Check-in.

No individual participant data will be shared

Neither the investigator nor the subject will know who has received the study drug or the placebo, The injections will be prepared by an unblinded pharmacist according to the randomization list.