Effects of Sirolimus on Asymptomatic ApoE4 Carriers

Inclusion Criteria: 1. Willing and able to provide informed consent 2. Sex assigned at birth: female 3. 45-65 years old 4. Able to perform self-care and activities of daily living with no or minimal assistance 5. Post-menopausal status or use of highly effective contraception. Post-menopausal is defined as either * 12 months of spontaneous amenorrhea with an appropriate clinical profile (e.g., age-appropriate, history of vasomotor symptoms) * surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks prior to screening. For oophorectomy alone, post-menopausal status must be confirmed by follow-up hormone level assessment * Highly effective contraception includes intrauterine devices (IUD), oral contraceptives, or other hormonal contraceptives including injectables, transdermal patches, implants or vaginal rings, or refraining from heterosexual intercourse during the 4 weeks of taking the study drug and for 2 weeks after no longer taking the study drug 6. Body weight of ≥ 40 kg 7. Ability to effectively communicate with the investigator and comply with study requirements Exclusion Criteria: 1. Diagnosis of mild cognitive impairment (MCI), dementia, or Alzheimer's disease 2. BMI ≥ 35 (based on MRI feasibility) 3. Type 1 diabetes or poorly controlled type 2 diabetes (HbA1c ≥ 6.5%) 4. History of skin ulcers or poor wound healing 5. Current tobacco or illicit drug use or alcohol abuse (defined as ≥ 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. Required use of medications that affect cytochrome P450 3A4 (CYP3A4) or alter cerebral blood flow (see Appendix 1 for tables of excluded medications) 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, 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. History of malignancy within the past 2 years, with the following exceptions: * Localized basal cell or squamous cell carcinoma of the skin * Prostate cancer confined to the gland (AJCC stage T2N0M0 or better) * Cervical carcinoma in situ * Breast cancer localized to the breast 23. History of epilepsy