Effects of Sirolimus on Asymptomatic ApoE4 Carriers

NCT07728175 | Not Yet Recruiting Phase 1 FDA Drug

• 1 other identifier: 2134312
• Study Type: interventional
• Target: 225
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Healthy Volunteer; Genetic Predisposition to Disease; APOE-4 Positive

Keywords

ApoE4 positive; Cerebral Blood Flow; Sirolimus; Rapamycin; Magnetic Resonance Imaging

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Measure the change in plasma Marker-cytokine using a Meso Scale Discovery (MSD) analyzer.

  Baseline to 4 weeks

• Measure baseline to post-treatment changes in Plasma Markers-AD pathology using a Meso Scale Discovery (MSD) analyzer

  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

Study Arms (2)

Sirolimus

ACTIVE COMPARATOR

Drug: Sirolimus (rapamycin)

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Sirolimus (rapamycin) DRUG

Participants in Sirolimus arm will receive Sirolimus.

Sirolimus

Placebo DRUG

Participants in the Placebo arm will receive Placebo

Placebo

Eligibility Criteria

• Age: 45 Years - 65 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide informed consent
• Sex assigned at birth: female
• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Missouri-Columbia: lead

Study Sites (1)

University of Missouri

Columbia, Missouri, 65212, United States

Location

Related Publications (10)

• 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 BACKGROUND

• 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.

  PMID: 40166019 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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.

  PMID: 20376313 BACKGROUND

• 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.

  PMID: 32173556 BACKGROUND

MeSH Terms

Conditions

Genetic Predisposition to Disease

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Disease Susceptibility; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Ai-Ling Lin, PhD

  University of Missouri-Columbia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kim Ray

CONTACT

573-884-5372; umhsradstudycoordinators@health.missouri.edu

Nathan Bresette

CONTACT

nbhtd@missouri.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Radiology

Study Record Dates

• First Submitted: July 16, 2026
• First Posted: July 27, 2026
• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): July 7, 2028
• Last Updated: July 30, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)