Effects of Sirolimus on Asymptomatic ApoE4 Carriers

Inclusion Criteria

• Willing and able to provide informed consent
• Sex assigned at birth: female
• 45-65 years old
• Able to perform self-care and activities of daily living with no or minimal assistance
• 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
• Body weight of ≥ 40 kg
• Ability to effectively communicate with the investigator and comply with study requirements

Exclusion Criteria

• Diagnosis of mild cognitive impairment (MCI), dementia, or Alzheimer's disease
• BMI ≥ 35 (based on MRI feasibility)
• Type 1 diabetes or poorly controlled type 2 diabetes (HbA1c ≥ 6.5%)
• History of skin ulcers or poor wound healing
• Current tobacco or illicit drug use or alcohol abuse (defined as ≥ 3 per day or ≥ 7 per week for women) (Per NIAAA guidelines)
• Use of anti-platelet or anti-coagulant medications other than aspirin
• Required use of medications that affect cytochrome P450 3A4 (CYP3A4) or alter cerebral blood flow (see Appendix 1 for tables of excluded medications)
• Immunosuppressant therapy within the last year
• Chemotherapy or radiation treatment within the last year
• Current or chronic history of liver or kidney disease or known hepatic or biliary abnormalities
• Untreated hypertriglyceridemia (fasting triglycerides \< 300 mg/dl)
• Current or chronic significant history of pulmonary disease
• Chronic heart failure
• Pregnancy or lactation
• Recent history (past six months) of myocardial infarction, active coronary artery disease, intestinal disorders, stroke, or transient ischemic attack
• Poorly controlled blood pressure (systolic BP > 160 or diastolic BP > 100 mmHg)
• Active inflammatory, COVID-19, autoimmune, infectious, hepatic, gastrointestinal, malignant, and/or severe mental illness
• History of, or MRI, or CT positive for, any space occupying brain lesion, including mass effect or abnormal intracranial pressure
• Organ transplant recipients
• History of Stroke
• History of ruptured intracranial aneurysm
• 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
• History of epilepsy