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

NCT05386914 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: 2091042
• Study Type: interventional
• Target: 205
• Locations: 1 country
• Sites: 1

Brief 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. 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. 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.

Conditions

Healthy Volunteers; Genetic Predisposition to Disease

Outcome Measures

Primary Outcomes (1)

• Change in Cerebral Blood Flow as measured on MRI

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

  Baseline to 4 weeks

Secondary Outcomes (5)

• Part I: Plasma and Microbiome Biomarkers

  Part I: Baseline to 4 weeks

• Part I: Plasma and Microbiome Markers

  Part I: Baseline to 4 weeks

• Part I: Plasma and Microbiome Biomarkers

  Part I: Baseline to 4 weeks

• Part I: Plasma and Microbiome Markers

  Part I: Baseline to 4 weeks

• Part II: RBC/Membrane Ratio

  Part II: Baseline to 4 weeks

Study Arms (2)

Carrier APOE4

EXPERIMENTAL

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. 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.

Drug: Sirolimus

Non-Carrier APOE4

OTHER

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. 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.

Drug: Sirolimus

Interventions

Sirolimus DRUG

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.

Carrier APOE4; Non-Carrier APOE4

Eligibility Criteria

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

You may qualify if:

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

You may not qualify if:

• \. Diagnosis of mild cognitive impairment (MCI) or dementia, including Alzheimer's disease
• \. BMI ≥35 (based on MRI feasibility)
• \. Diabetes (HBA1c≥6.5% or antidiabetic medications)
• \. History of skin ulcers or poor wound healing
• \. 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)
• \. Use of anti-platelet or anti-coagulant medications other than aspirin
• \. Current medications that affect cytochrome P450 3A4 (CYP3A4)
• \. 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

Columbia, Missouri, 65212, United States

Location

Related Publications (14)

• 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.

  PMID: 26346644 BACKGROUND

• 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.

  PMID: 18695059 BACKGROUND

• 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

• 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.

  PMID: 29408453 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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.

  PMID: 26721390 BACKGROUND

• 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.

  PMID: 23801246 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

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: May 16, 2022
• First Posted: May 23, 2022
• Study Start: March 2, 2023
• Primary Completion: September 19, 2025
• Study Completion (Estimated): December 1, 2027
• Last Updated: March 6, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)