This Study Consists of Two Study Parts Conducted Under a Single IRB. Part I: Short Term ApoE-dependent Cerebral Blood Flow Response to Sirolimus in Cognitively Normal Adults Part II: Short Term ApoE-dependent Cerebral Blood Flow and Lung Perfusion Response to Sirolimus in Cognitively Normal Adults

This study consisted of two separate study parts conducted under the same IRB approval. Part I and Part II were operationally distinct but administratively linked.

Part I:

Inclusion Criteria:

• 1. Age 45-65 y/o
• 2. Male or female, all ethnic groups
• 3. Montreal Cognitive Assessment (MoCA) score greater than or equal to 26
• 4. Clinical Dementia Rating (CDR) Staging Instrument = 0
• 5. Carrier Cohort: APOE4 homozygous or heterozygous
• 6. Non-Carrier cohort: no APOE4 gene identified

Exclusion Criteria:

• 1. Diagnosis of mild cognitive impairment (MCI) or dementia, including Alzheimer'sdisease
• 2. BMI ≥35 (based on MRI feasibility)
• 3. Diabetes (HBA1c≥6.5% or antidiabetic medications)
• 4. History of skin ulcers or poor wound healing
• 5. Current tobacco or illicit drug use or alcohol abuse (defined as ≥4 per day or ≥14 per week for men and ≥3 per day or ≥7 per week for women) (Per NIAAA guidelines)
• 6. Use of anti-platelet or anti-coagulant medications other than aspirin
• 7. Current medications that affect cytochrome P450 3A4 (CYP3A4)
• 8. Immunosuppressant therapy within the last year
• 9. Chemotherapy or radiation treatment within the last year
• 10. Current or chronic history of liver or kidney disease or known hepatic orbiliary abnormalities
• 11. Untreated hypertriglyceridemia (fasting triglycerides < 300 mg/dl)
• 12. Current or chronic significant history of pulmonary disease
• 13. Chronic heart failure
• 14. Pregnancy or lactation
• 15. Recent history (past six months) of myocardial infarction, active coronaryartery disease, intestinal disorders, stroke, or transient ischemic attack
• 16. Poorly controlled blood pressure (systolic BP>160 or diastolic BP>100 mmHg)

• 17.Active inflammatory, Coronavirus (COVID-19), autoimmune, infectious, hepatic,gastrointestinal, malignant, and/or severe mental illness

• 18. History of, or MRI, or CT positive for, any space occupying brain lesion,including mass effect or abnormal intracranial pressure
• 19. Organ transplant recipients
• 20. History of Stroke
• 21. History of ruptured intracranial aneurysm
• 22. Any condition for which a MRI procedure is contraindicated. Some examplesinclude: metallic material in the body, such as pacemakers, metallic clips, etc.
• 23. Likelihood of claustrophobia

Part II:

The inclusion and exclusion criteria for Part I apply to Part II with the addition of the following:

Exclusion Criteria:

1. Baseline oxygen requirement

2. Blood oxygen saturation of 90% or less than as measured by pulse oximetry on the dayof imaging

3. FEV1 percent predicted less than 25%

4. Claustrophobia, inner ear implants, aneurysm or other surgical clips, metal foreignbodies in the eye, pacemaker or other contraindication to MR scanning. Subjects withany implanted device that cannot be verified as MRI compliant will be excluded

5. Chest circumference greater than that of the xenon-129 MR coil. The circumference ofthe coil is approximately 42 inches

6. History of congenital cardiac disease or history of apneic episodes

7. Inability to understand simple instructions or to hold still for approximately 10seconds

8. History of respiratory infection within 2 weeks prior to the MR scan