Short Term Sirolimus Treatment and MRI of the Brain

Study Overview
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Brief Summary
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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. 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.

Official Title
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Short Term Apolipoprotein E (ApoE)-Dependent Cerebral Blood Flow Response to Sirolimus in Cognitively Normal Adults

Conditions
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Genetic Predisposition to Disease, Healthy Volunteers

Intervention / Treatment
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* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carrier APOE4<br> | Drug: Sirolimus<br>* 1 mg of Sirolimus taken orally once a day for 4 weeks.<br>|
| Other: Non-Carrier APOE4<br> | Drug: Sirolimus<br>* 1 mg of Sirolimus taken orally once a day for 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cerebral blood flow as measured on MRI after 4 weeks of Sirolimus | Rate of blood perfusion expressed as mL/g/min in hippocampus | Assessed at Visit 2 immediately before starting sirolimus and Visit 4 after 4 weeks of continuous sirolimus |