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Genetic Predisposition to DiseasePhase 1NCT05386914

This Study Consists of Two Study Parts Conducted Under a Single IRB. Part I: Short Term ApoE-dependent Cerebral Blood Flow Response to Sirolimus in Cognitively Normal Adults Part II: Short Term ApoE-dependent Cerebral Blood Flow and Lung Perfusion Response to Sirolimus in Cognitively Normal Adults

A Phase 1 study testing Sirolimus in people with Genetic Predisposition to Disease and Healthy Volunteers, run by University of Missouri-Columbia at 1 site in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

This study consists of two study parts (Part I and Part II) conducted under a single IRB approval. Individuals that participated in Part I of the study were invited to participate in Part II of the study. Read more about this study

Who is it for?
Ages 45 to 65 yearsHealthy volunteers can take part
What is being tested?
Sirolimus
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
205 participants
Where
1 siteUnited States
Study dates
2 Mar 2023to Dec 2027
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 45 to 65 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • 1. Age 45-65 y/o
  • 2. Male or female, all ethnic groups
  • 3. Montreal Cognitive Assessment (MoCA) score greater than or equal to 26
  • 4. Clinical Dementia Rating (CDR) Staging Instrument = 0
  • 5. Carrier Cohort: APOE4 homozygous or heterozygous
  • 6. Non-Carrier cohort: no APOE4 gene identified

Who cannot join

  • 1. Diagnosis of mild cognitive impairment (MCI) or dementia, including Alzheimer's disease
  • 2. BMI ≥35 (based on MRI feasibility)
  • 3. Diabetes (HBA1c≥6.5% or antidiabetic medications)
  • 4. History of skin ulcers or poor wound healing
  • 5. Current tobacco or illicit drug use or alcohol abuse (defined as ≥4 per day or ≥14 per week for men and ≥3 per day or ≥7 per week for women) (Per NIAAA guidelines)
  • 6. Use of anti-platelet or anti-coagulant medications other than aspirin
Show all 33Show fewer
  • 7. Current medications that affect cytochrome P450 3A4 (CYP3A4)
  • 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, Coronavirus (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. Any condition for which a MRI procedure is contraindicated. Some examples include: metallic material in the body, such as pacemakers, metallic clips, etc.
  • 23. Likelihood of claustrophobia
  • Part II:
  • The inclusion and exclusion criteria for Part I apply to Part II with the addition of the following:
  • Baseline oxygen requirement
  • Blood oxygen saturation of 90% or less than as measured by pulse oximetry on the day of imaging
  • FEV1 percent predicted less than 25%
  • Claustrophobia, inner ear implants, aneurysm or other surgical clips, metal foreign bodies in the eye, pacemaker or other contraindication to MR scanning. Subjects with any implanted device that cannot be verified as MRI compliant will be excluded
  • Chest circumference greater than that of the xenon-129 MR coil. The circumference of the coil is approximately 42 inches
  • History of congenital cardiac disease or history of apneic episodes
  • Inability to understand simple instructions or to hold still for approximately 10 seconds
  • History of respiratory infection within 2 weeks prior to the MR scan

Trial locations and contacts

1 site in 1 country.

United States1 site

  • University of Missouri-Columbia

    Columbia, Missouri, 65212

Other trials in United States

About this study

Official title: Part I: Short Term ApoE-dependent Cerebral Blood Flow Response to Sirolimus in Cognitively Normal Adults Part II: Short Term ApoE-dependent Cerebral Blood Flow and Lung Perfusion Response to Sirolimus in Cognitively Normal Adults

This study consists of two study parts (Part I and Part II) conducted under a single IRB approval. Individuals that participated in Part I of the study were invited to participate in Part II of the study.

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 is an FDA-approved medication which may improve the blood flow to the brain.

Read more

Part I: This study is designed to see if sirolimus treatment improves MRI blood flow to the brain in individuals with and without a genetic predisposition to Alzheimer's disease. Part I of this study is complete and no longer enrolling participants.

Part II: Ongoing research will expand the genetic predisposition cohort and further explore the drug's impact on the lung perfusion via hyperpolarized xenon-129 gas MRI and the brain-vascular connection. Only subjects who are APOE4 carriers will be enrolled in Part II.

Hyperpolarized xenon-129 gas MRI is a non-invasive technique in which a subject inhales a bolus of hyperpolarized xenon-129 gas which can be directly imaged by the MRI as it physiologically distributes itself throughout the lung interior and within tissue and red blood cells. It thus allows for direct imaging and quantification of regional lung function: ventilation, gas-exchange, and perfusion. The relationship between pulmonary vascular function and brain perfusion is largely unstudied. We hope to investigate the relationship between pulmonary vascular function and cerebral blood flow by quantifying both lung and brain perfusion before and after the administration of Sirolimus.

Being tested
Sirolimus
Medical subject headings
Genetic Predisposition to Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • SirolimusDrug

    This study consisted of two separate study parts conducted under the same IRB approval. Part I and Part II were operationally distinct but administratively linked.

    During Part I and Part II of the study, 1 mg of Sirolimus was taken orally once a day for 4 weeks.

Study groups in NCT05386914
Study groupRoleWhat they receive
Carrier APOE4ExperimentalThis study consisted of two separate study parts conducted under the same IRB approval. Part I and Part II were operationally distinct but administratively linked. For Part I and Part II of this study, the experimental arm consisted of individuals that carried the APOE4 gene. Individuals that carried the APOE4 gene, and participated in Part I of the study, were invited to participate in Part II of the study.
Receives: Drug: Sirolimus
Non-Carrier APOE4OtherThis study consisted of two separate study parts conducted under the same IRB approval. Part I and Part II were operationally distinct but administratively linked. For Part I ONLY of this study, the second arm consisted of individuals that did not carry the APOE4 gene. Individuals that participated in Part I of the study, and did not carry the APOE4 gene, were not invited to participate in Part II of the study.
Receives: Drug: Sirolimus

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Cerebral Blood Flow as measured on MRI

    Rate of blood perfusion expressed as mL/100g/min globally and regionally

    Measured: Baseline to 4 weeks

Secondary outcomes (5)

  1. Part I: Plasma and Microbiome Biomarkers

    Part I: To assess baseline-to-post-treatment changes in plasma metabolomics and short-chain-fatty-acids (SCFA) profiles

    Measured: Part I: Baseline to 4 weeks

  2. Part I: Plasma and Microbiome Markers

    Part I: To assess baseline-to-post-treatment changes in plasma markers associated with AD pathology

    Measured: Part I: Baseline to 4 weeks

  3. Part I: Plasma and Microbiome Biomarkers

    Part I: To assess baseline-to-post-treatment changes in plasma cytokine levels

    Measured: Part I: Baseline to 4 weeks

  4. Part I: Plasma and Microbiome Markers

    Part I: To assess baseline-to-post-treatment gut microbiome diversity and composition

    Measured: Part I: Baseline to 4 weeks

  5. Part II: RBC/Membrane Ratio

    Part II: In addition to the outcome measures listed for Part I of this study, the secondary outcome measures for Part II are as follows: ratio of xenon signal dissolved in RBCs to xenon signal dissolved in membrane tissues

    Measured: Part II: Baseline to 4 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 May 2022
  2. Study start2 Mar 2023
  3. Primary completion19 Sep 2025
  4. Study completionDec 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Basic science
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Investigator
Enrolment
205 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05386914
Sponsor's protocol ID
2091042
Status last verified
Mar 2026
First submitted
16 May 2022
Last updated
6 Mar 2026
Results posted
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Trzepacz PT, Hochstetler H, Wang S, Walker B, Saykin AJ; Alzheimer's Disease Neuroimaging Initiative. Relationship between the Montreal Cognitive Assessment and Mini-mental State Examination for assessment of mild cognitive impairment in older adults. BMC Geriatr. 2015 Sep 7;15:107. doi: 10.1186/s12877-015-0103-3.

    PubMed 26346644

  • O'Bryant SE, Waring SC, Cullum CM, Hall J, Lacritz L, Massman PJ, Lupo PJ, Reisch JS, Doody R; Texas Alzheimer's Research Consortium. Staging dementia using Clinical Dementia Rating Scale Sum of Boxes scores: a Texas Alzheimer's research consortium study. Arch Neurol. 2008 Aug;65(8):1091-5. doi: 10.1001/archneur.65.8.1091.

    PubMed 18695059

  • 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.

    PubMed 17708140

  • Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, Benavides AD, Curiel TJ, Javors MA, Musi N, Chiodo L, Koek W, Gelfond JAL, Kellogg DL Jr. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol. 2018 May;105:53-69. doi: 10.1016/j.exger.2017.12.026. Epub 2018 Feb 3.

    PubMed 29408453

  • 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.

    PubMed 23667480

  • 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.

    PubMed 20376313

  • 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.

    PubMed 26568298

  • 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.

    PubMed 25038772

  • 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.

    PubMed 30311681

  • 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.

    PubMed 27341957

  • 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.

    PubMed 32173556

  • Lin AL, Jahrling JB, Zhang W, DeRosa N, Bakshi V, Romero P, Galvan V, Richardson A. Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer's disease. J Cereb Blood Flow Metab. 2017 Jan;37(1):217-226. doi: 10.1177/0271678X15621575. Epub 2015 Dec 31.

    PubMed 26721390

  • Lin AL, Zheng W, Halloran JJ, Burbank RR, Hussong SA, Hart MJ, Javors M, Shih YY, Muir E, Solano Fonseca R, Strong R, Richardson AG, Lechleiter JD, Fox PT, Galvan V. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease. J Cereb Blood Flow Metab. 2013 Sep;33(9):1412-21. doi: 10.1038/jcbfm.2013.82. Epub 2013 Jun 26.

    PubMed 23801246

  • 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.

    PubMed 25540326

  • Aware C, Neher CM, Woods C, Khegai O, Dwivedi AK, Govindarajan M, Ivanich K, Kurt M, Beversdorf D, Cheng J, Bresette N, Cui T, Balchandani P, Gonzales MM, Ericsson AC, Altes TA, Lin AL. Rapamycin increases cerebral blood flow and modulates metabolic, inflammatory, and microbiome profiles in healthy middle-aged APOE4 carriers: A pilot single-arm trial. J Cereb Blood Flow Metab. 2026 Sep 10:271678X261490342. doi: 10.1177/0271678X261490342. Online ahead of print.

    PubMed 42723264

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Sirolimus in people with Genetic Predisposition to Disease and Healthy Volunteers, run by University of Missouri-Columbia at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 6 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Cerebral Blood Flow as measured on MRI (time frame: Baseline to 4 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05386914, which also lists 15 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Mar 2026.

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