Effects of Sirolimus on Asymptomatic ApoE4 Carriers

Effects of Sirolimus on Middle Aged Asymptomatic ApoE4 Carriers

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

Study Overview

• Status: Not yet recruiting
• Conditions: Genetic Predisposition to Disease; Healthy Volunteer; APOE-4 Positive
• Intervention / Treatment: Drug: Sirolimus (rapamycin); Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 225
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Kim Ray; Phone Number: 573-884-5372; Email: umhsradstudycoordinators@health.missouri.edu
• Study Contact Backup: Name: Nathan Bresette; Email: nbhtd@missouri.edu

Study Locations

• United States
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri
      • Principal Investigator: Ai-Ling Lin, PhD
      • Contact: Nathan Bresette; Email: nbhtd@missouri.edu
      • Contact: Kim Ray; Phone Number: 573-884-5372; Email: raykk@health.missouri.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Participants in the Placebo arm will receive Placebo
Active Comparator: Sirolimus	Drug: Sirolimus (rapamycin); Participants in Sirolimus arm will receive Sirolimus.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cerebral Blood Flow as measured by MRI	Rate of blood perfusion expressed as mL/100g/min globally and regionally	Baseline to 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure the change in plasma Marker-cytokine from baseline to post-treatment		Baseline to 4 weeks
Measure baseline to post-treatment changes in Plasma Markers-AD pathology		Baseline to 4 weeks
Measure brain function connectivity by fMRI		Baseline to 4 weeks
Measurement of blood brain barrier by MRI		Baseline to 4 weeks
Measurement of brain oxygenation by MRI		Baseline to 4 weeks
Measurement of glucose uptake in the brain by PET imaging	Glucose uptake in the brain globally and regionally	Baseline to 4 weeks

Collaborators and Investigators

• Sponsor: University of Missouri-Columbia
• Collaborators: Altos Labs
• Investigators: Principal Investigator: Ai-Ling Lin, PhD, University of Missouri-Columbia

Publications and helpful links

General 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Lin AL, Parikh I, Yanckello LM, White RS, Hartz AMS, Taylor CE, McCulloch SD, Thalman SW, Xia M, McCarty K, Ubele M, Head E, Hyder F, Sanganahalli BG. APOE genotype-dependent pharmacogenetic responses to rapamycin for preventing Alzheimer's disease. Neurobiol Dis. 2020 Jun;139:104834. doi: 10.1016/j.nbd.2020.104834. Epub 2020 Mar 12.
• 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.
• Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS One. 2010 Apr 1;5(4):e9979. doi: 10.1371/journal.pone.0009979.
• 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. doi: 10.21203/rs.3.rs-6214340/v1.

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): July 7, 2028

Study Registration Dates

• First Submitted: July 16, 2026
• First Submitted That Met QC Criteria: July 21, 2026
• First Posted (Actual): July 27, 2026

Study Record Updates

• Last Update Posted (Actual): July 27, 2026
• Last Update Submitted That Met QC Criteria: July 21, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Magnetic Resonance Imaging; Sirolimus; Rapamycin; Cerebral Blood Flow; ApoE4 positive
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Disease Susceptibility; Pathological Conditions, Signs and Symptoms; Genetic Predisposition to Disease; Organic Chemicals; Macrolides; Lactones; Sirolimus
• Other Study ID Numbers: 2134312

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No