Effects of Sirolimus on Asymptomatic ApoE4 Carriers

Official title

Effects of Sirolimus on Middle Aged Asymptomatic ApoE4 Carriers

Overview

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 (Rapamycin) is an FDA-approved medication which may improve the blood flow to the brain. The purpose of the clinical trial is to find out whether sirolimus can help improve blood flow and energy use in the brain in women ages 45 to 65 who have the ApoE4 gene, a gene which increases the risk of developing Alzheimer's disease later in life. There will be two arms in this trail, a sirolimus arm and a placebo arm. A placebo is a pill that looks like the study drug, but it does not have any real medicine in it. Participants will be randomized to one arm or the other, but not to both arms. Three study visits over a 12-week period are required. Participants will: (i) Complete some questionnaires about how well you think; (ii) Complete genetic testing for the ApoE4 gene; (iii) Have blood work, blood pressure and height and weight collected; (iv) Take either Sirolimus or a placebo daily, by mouth, for approximately 4 weeks; (v) Keep a diary of when the sirolimus or placebo is taken; (vi) Complete 2 Magnetic Resonance Imaging (MRI) exams

Interventions

• Drug Sirolimus (rapamycin)
  Participants in Sirolimus arm will receive Sirolimus.
• Drug Placebo
  Participants in the Placebo arm will receive Placebo

Primary outcome measures

• Change in Cerebral Blood Flow as measured by MRI [Time frame: Baseline to 4 weeks]

Secondary outcome measures (6)

• Measure the change in plasma Marker-cytokine using a Meso Scale Discovery (MSD) analyzer. [Time frame: Baseline to 4 weeks]
• Measure baseline to post-treatment changes in Plasma Markers-AD pathology using a Meso Scale Discovery (MSD) analyzer [Time frame: Baseline to 4 weeks]
• Measure brain function connectivity by fMRI [Time frame: Baseline to 4 weeks]
• Measurement of blood brain barrier by MRI [Time frame: Baseline to 4 weeks]
• Measurement of brain oxygenation by MRI [Time frame: Baseline to 4 weeks]
• Measurement of glucose uptake in the brain by PET imaging [Time frame: Baseline to 4 weeks]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Basic science

Study locations

United States · 1 center

• University of Missouri — Columbia

Publications

• Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007 Aug 1;76(3):391-6. PMID 17708140
• Lin AL, Aware C, Neher C, Hamdi M, Ericsson A, Khegai O, Patrie J, Kurt M, Govindarajan M, Woods C, Ivanich K, Beversdorf D, Cheng J, Balchandani P, Gonzales M, Altes T. Rapamycin enhances neurovascular, peripheral metabolic, and immune function in cognitively normal, middle-aged APOE4 Carriers: genotype-dependent effects compared to non-carriers. Res Sq [Preprint]. 2025 Mar 19:rs.3.rs-6214340. do PMID 40166019
• Ozcelik S, Fraser G, Castets P, Schaeffer V, Skachokova Z, Breu K, Clavaguera F, Sinnreich M, Kappos L, Goedert M, Tolnay M, Winkler DT. Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. PLoS One. 2013 May 7;8(5):e62459. doi: 10.1371/journal.pone.0062459. Print 2013. PMID 23667480
• Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014 Dec 24;6(268):268ra179. doi: 10.1126/scitranslmed.3009892. PMID 25540326
• Lelegren M, Liu Y, Ross C, Tardif S, Salmon AB. Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate. Pathobiol Aging Age Relat Dis. 2016 Jun 23;6:31793. doi: 10.3402/pba.v6.31793. eCollection 2016. PMID 27341957
• Sills AM, Artavia JM, DeRosa BD, Ross CN, Salmon AB. Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets. Am J Primatol. 2019 Feb;81(2):e22927. doi: 10.1002/ajp.22927. Epub 2018 Oct 12. PMID 30311681
• Tardif S, Ross C, Bergman P, Fernandez E, Javors M, Salmon A, Spross J, Strong R, Richardson A. Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset. J Gerontol A Biol Sci Med Sci. 2015 May;70(5):577-87. doi: 10.1093/gerona/glu101. Epub 2014 Jul 19. PMID 25038772
• Ross C, Salmon A, Strong R, Fernandez E, Javors M, Richardson A, Tardif S. Metabolic consequences of long-term rapamycin exposure on common marmoset monkeys (Callithrix jacchus). Aging (Albany NY). 2015 Nov;7(11):964-73. doi: 10.18632/aging.100843. PMID 26568298

Identifiers

NCT: NCT07728175 · 2134312

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗