This study consists of two study parts (Part I and Part II) conducted under a single IRB approval. Individuals that participated in Part I of the study were invited to participate in Part II of the study.

Alzheimer's disease is a devastating neurodegenerative disease characterized by accumulation of clumps (also called plaques) and bundles of fibers (also called tangles) in the brain, for which there is currently no cure. Sirolimus is an FDA-approved medication which may improve the blood flow to the brain.

Part I: This study is designed to see if sirolimus treatment improves MRI blood flow to the brain in individuals with and without a genetic predisposition to Alzheimer's disease. Part I of this study is complete and no longer enrolling participants.

Part II: Ongoing research will expand the genetic predisposition cohort and further explore the drug's impact on the lung perfusion via hyperpolarized xenon-129 gas MRI and the brain-vascular connection. Only subjects who are APOE4 carriers will be enrolled in Part II.

Hyperpolarized xenon-129 gas MRI is a non-invasive technique in which a subject inhales a bolus of hyperpolarized xenon-129 gas which can be directly imaged by the MRI as it physiologically distributes itself throughout the lung interior and within tissue and red blood cells. It thus allows for direct imaging and quantification of regional lung function: ventilation, gas-exchange, and perfusion. The relationship between pulmonary vascular function and brain perfusion is largely unstudied. We hope to investigate the relationship between pulmonary vascular function and cerebral blood flow by quantifying both lung and brain perfusion before and after the administration of Sirolimus.

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's disease
• 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 or biliary 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 coronary artery 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 examples include: 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 day of imaging
3. FEV1 percent predicted less than 25%
4. Claustrophobia, inner ear implants, aneurysm or other surgical clips, metal foreign bodies in the eye, pacemaker or other contraindication to MR scanning. Subjects with any 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 of the 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 10 seconds
8. History of respiratory infection within 2 weeks prior to the MR scan