Rapamycin for Alzheimer's Disease

(REACH Trial)

Overseen By Sudha Seshadri, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: The University of Texas Health Science Center at San Antonio

Must be taking: AD medications

Must not be taking: Antidiabetics, Anticoagulants, CYP3A4 drugs

Disqualifiers: Diabetes, Liver disease, Heart failure, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 52 weeks

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This study will evaluate the safety, tolerability, and feasibility of 12 month oral rapamycin treatment in older adults with amnestic mild cognitive impairment (aMCI) and early stage Alzheimer's disease (AD).

Will I have to stop taking my current medications?

The trial requires that participants have a stable dose of Alzheimer's medications like Donepezil, rivastigmine, Memantine, or galantamine for at least three months. However, you cannot participate if you are taking medications that affect cytochrome 450 3A4 (CYP3A4) or certain other medications. It's best to discuss your current medications with the trial team to see if any changes are needed.

Is rapamycin generally safe for human use?

Rapamycin, also known as sirolimus, has been used safely as an immunosuppressant in kidney transplant patients and has a lower risk of kidney, nerve, and certain cancer-related complications compared to other similar drugs. However, it can increase lipid levels (fats in the blood), especially in people with existing high cholesterol. ^{1 2 3 4 5}

How does the drug Rapamycin differ from other Alzheimer's treatments?

Rapamycin is unique because it targets the mTOR pathway, which helps clear toxic protein build-up in the brain, such as amyloid-beta and tau, through a process called autophagy (cellular cleanup). This mechanism may help improve cognitive function and reduce Alzheimer's disease symptoms, setting it apart from other treatments that do not focus on this pathway. ^{5 6 7 8 9}

What evidence supports the effectiveness of the drug Rapamycin for Alzheimer's disease?

Research shows that Rapamycin, an mTOR inhibitor, can improve cognitive function and reduce harmful protein deposits in the brain in mouse models of Alzheimer's disease. This suggests it might help delay the progression of Alzheimer's by targeting specific brain changes associated with the disease. ^{2 3 5 10 11}

Who Is on the Research Team?

Sudha J Seshadri, MD

Principal Investigator

UT Health San Antonio

Mitzi J Gonzales, PhD

Principal Investigator

UT Health San Antonio

Are You a Good Fit for This Trial?

Adults aged 55-89 with mild cognitive impairment or early Alzheimer's, who have a representative to assist them and are on stable Alzheimer's medication. They must show amyloid presence in PET imaging, have normal organ function and blood counts, and controlled glucose levels. Excluded are those with recent severe illnesses, immunosuppressant use, untreated high triglycerides, heart issues, certain neurological conditions other than AD/MCI.

Inclusion Criteria

My gender or ethnicity does not limit my participation.

I am between 55 and 89 years old.

Labs: Normal blood cell counts without clinically significant excursions; normal liver and renal function; and glucose control (HbA1c < 6.5%). Fasting lipid panel and prothrombin time/prothrombin time test/international normalized ration (PT/PTT/INR) within normal limits

Exclusion Criteria

Current tobacco or illicit drug use or alcohol abuse

I have diabetes with HBA1c levels of 6.5% or higher, or I am on medication for it.

Untreated hypertriglyceridemia (fasting triglycerides < 250 mg/dl)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

12 weeks

1 visit (in-person)

Treatment

Participants receive oral rapamycin or placebo for 12 months

52 weeks

Monthly visits (in-person)

Post-treatment assessment

Assessment completed within 14 days of the final study drug dose

2 weeks

1 visit (in-person)

Follow-up

Final assessment conducted 6 months after the final study drug dose

26 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Rapamycin

Trial Overview The trial is testing the safety of rapamycin over a year in older adults with memory loss due to mild cognitive impairment or early Alzheimer's disease. Participants will either receive rapamycin or a placebo (a substance with no therapeutic effect) to compare outcomes.

How Is the Trial Designed?

Group I: RAPA (rapamycin) treatment group Active Control 1 Intervention

Subjects will receive active drug

Group II: Placebo group Placebo Group 1 Intervention

Subjects will receive placebo

Rapamycin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Rapamune for:

• Prevention of organ transplant rejection
• Lymphangioleiomyomatosis
• Perivascular epithelioid cell tumors

Approved in United States as Rapamune for:

• Prevention of organ transplant rejection
• Lymphangioleiomyomatosis
• Perivascular epithelioid cell tumors

Approved in Canada as Rapamune for:

• Prevention of organ transplant rejection
• Lymphangioleiomyomatosis

Approved in Japan as Rapamune for:

• Prevention of organ transplant rejection

Who Is Running the Clinical Trial?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

Published Research Related to This Trial

Rapamycin, a macrolide antibiotic and mTOR inhibitor, has shown promise in various Alzheimer's disease models by potentially delaying disease progression through mechanisms like reducing β-amyloid deposition and inhibiting tau protein hyperphosphorylation.

Despite its therapeutic potential, the effectiveness of rapamycin in Alzheimer's treatment is still debated due to variability in experimental conditions, including model types, administration methods, and dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin Responds to Alzheimer's Disease: A Potential Translational Therapy. Hou, SJ., Zhang, SX., Li, Y., et al.[2023]

Sirolimus (rapamycin) is an effective immunosuppressant approved for preventing graft rejection in kidney transplants, with a lower risk of complications compared to other immunosuppressants.

Recent findings suggest that sirolimus may also have potential in treating skin disorders and extending lifespan, making it a promising candidate for addressing age-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. Peters, T., Traboulsi, D., Tibbles, LA., et al.[2014]

Everolimus, an mTOR inhibitor, was found to effectively reduce Alzheimer's disease pathology and improve cognitive function in a mouse model (3×Tg-AD mice) when administered directly into the brain, showing promise as a potential treatment for early stages of Alzheimer's.

The study demonstrated that everolimus has higher stability and effectiveness in the central nervous system when delivered directly into the brain compared to peripheral administration, with minimal impact on peripheral organs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early intrathecal infusion of everolimus restores cognitive function and mood in a murine model of Alzheimer's disease. Cassano, T., Magini, A., Giovagnoli, S., et al.[2019]

Sirolimus is a powerful immunosuppressant used in kidney transplantation that works by inhibiting the mTOR pathway, which is crucial for cell growth and proliferation, leading to reduced rates of acute rejection episodes to less than 10% when combined with cyclosporin A (CsA).

In clinical trials, using sirolimus at doses of 2 or 5 mg/day alongside CsA and steroids resulted in acute rejection rates of only 19% and 14% within 12 months, while also potentially reducing the need for nephrotoxic calcineurin inhibitors, although it may cause side effects like myelosuppression and increased lipid levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. Kahan, BD.[2019]

Rapamycin, an mTOR inhibitor, significantly improved cognitive dysfunction in mice with Alzheimer's disease induced by amyloid β(1-42), as evidenced by better performance in maze tests over a 14-day treatment period.

The treatment with rapamycin reduced levels of amyloid β(1-42) and increased Homer3 expression in the hippocampus, suggesting that its mechanism of action involves modulating mTOR phosphorylation and enhancing synaptic function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of mammalian target of rapamycin on cognitive dysfunction of Alzheimer's Disease via regulating Homer3]. Huang, YQ., Liu, XG., Zhang, L., et al.[2021]

In a phase 1 study involving 32 pediatric patients on dialysis, sirolimus was found to be well tolerated with no serious adverse events reported, indicating its safety for use in this population.

Younger patients (ages 5-11) showed significantly higher clearance rates of sirolimus compared to older patients (ages 12-18), suggesting they may need higher maintenance doses to achieve similar drug levels as healthy adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. Tejani, A., Alexander, S., Ettenger, R., et al.[2022]

Sirolimus (RAPA) treatment in renal transplant patients significantly increases plasma triglyceride levels and VLDL-apoB100 concentrations due to a reduced catabolic rate of these lipoproteins, rather than increased production.

The study found that RAPA-induced hyperlipidemia is linked to decreased clearance of apoB100-containing lipoproteins, highlighting a metabolic pathway that could be targeted to manage lipid levels in patients undergoing immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Hoogeveen, RC., Ballantyne, CM., Pownall, HJ., et al.[2019]

Rapamycin, an mTOR inhibitor, shows promise as a potential treatment for Alzheimer's disease by enhancing autophagy, which helps clear toxic protein aggregates like amyloid β (Aβ) and reduces tau hyper-phosphorylation.

The neuroprotective effects of rapamycin may lead to improvements in cognitive function by addressing key pathological processes associated with Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin, Autophagy, and Alzheimer's Disease. Cai, Z., Yan, LJ.[2022]

Rapamycin treatment in OXYS rats, which exhibit early signs of aging, significantly improved behavior and prevented brain abnormalities, such as increased hippocampal area and hydrocephalus, compared to untreated rats.

The treatment also reduced neurodegeneration markers, including Tau and phospho-Tau levels, suggesting that low doses of rapamycin can effectively suppress brain aging without causing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin suppresses brain aging in senescence-accelerated OXYS rats. Kolosova, NG., Vitovtov, AO., Muraleva, NA., et al.[2021]

The study reveals that the accumulation of amyloid-beta (Abeta) in Alzheimer's disease increases mTOR signaling, which is linked to cognitive decline, suggesting a critical relationship between these two factors.

Using an animal model, the research demonstrates that the FDA-approved drug rapamycin can restore mTOR signaling, improve cognitive function, and reduce both Abeta and Tau pathology by enhancing autophagy, providing a potential therapeutic approach for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. Caccamo, A., Majumder, S., Richardson, A., et al.[2022]

The mTOR pathway is crucial for various brain functions, and its dysregulation is linked to Alzheimer's disease (AD), contributing to issues like the buildup of harmful proteins and disrupted neuronal metabolism.

mTOR inhibitors, such as rapamycin, show promise as potential treatments for AD by reducing key disease markers and improving cognitive function, but more research is needed to fully understand their effects and develop effective human therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting mTOR to reduce Alzheimer-related cognitive decline: from current hits to future therapies. Tramutola, A., Lanzillotta, C., Di Domenico, F.[2022]

Citations

1. New Zealand pubmed.ncbi.nlm.nih.gov

Rapamycin Responds to Alzheimer's Disease: A Potential Translational Therapy. [2023]

2. Canada pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. [2014]

3. United States pubmed.ncbi.nlm.nih.gov

Early intrathecal infusion of everolimus restores cognitive function and mood in a murine model of Alzheimer's disease. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. [2019]

5. China pubmed.ncbi.nlm.nih.gov

[Effect of mammalian target of rapamycin on cognitive dysfunction of Alzheimer's Disease via regulating Homer3]. [2021]

6. Denmark pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Rapamycin, Autophagy, and Alzheimer's Disease. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Rapamycin suppresses brain aging in senescence-accelerated OXYS rats. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Targeting mTOR to reduce Alzheimer-related cognitive decline: from current hits to future therapies. [2022]