Evaluating Rapamycin Treatment in Alzheimer's Disease Using Positron Emission Tomography (ERAP)

Evaluating Rapamycin Treatment in Alzheimer's Disease Using Positron Emission Tomography (ERAP)

This single-center, uncontrolled pilot study aims to evaluate the efficacy, safety, and tolerability of six months of intermittently dosed oral rapamycin (sirolimus) in subjects with early-stage Alzheimer's disease.

Fifteen participants will be recruited. Following a set of baseline measurements, all participants will receive a weekly oral dose of 7 mg rapamycin for six months. Participants will be continuously monitored for safety and side effects. At the termination of the treatment, follow-up measurements will be taken.

The primary endpoint will be change in cerebral glucose metabolism, measured using 18F labeled fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET).

In addition to the registered outcome measures this pilot trial will explore the feasibility of acquiring data on the effect of sirolimus treatment on age-related tissue changes in the body using a variety of imaging modalities, such as bone mineral density assessed using quantitative computed tomography, retinal structures assessed using optical coherence tomography, periodontal tissue assessed using MRI and FDG-PET, cardiac function assessed using MRI, vessel wall in large arteries using MRI and [18F]FDG PET.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Sirolimus

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Stockholm
    • Solna, Stockholm, Sweden, 171 64
      • Karolinska University Hospital Memory clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Clinical diagnosis of mild cognitive impairment (MCI), or dementia of Alzheimer's type
2. Amyloid positivity established with either amyloid positron emission tomography or cerebrospinal fluid analysis.

3. For subjects with dementia, the disease should be in an early stage, operationalized as:

   • Stage 4 (Mild dementia) or lower, according to the National Institute on Aging - Alzheimer's Association 2018 clinical staging criteria, AND
   • Clinical Dementia Rating Scale (CDR) global score of 1 or lower, AND
   • Montreal Cognitive Assessment (MoCA) score of ≥ 18 OR Rey Auditory Verbal Learning Test (RAVLT) >4 words after 30 minutes
4. Capable of giving, and has the capacity to give informed consent
5. Availability of a responsible study partner who can accompany the subject to all planned visits
6. Male or female between 50 and 80 years
7. Normal or clinically acceptable medical history, physical examination, and vital signs

Exclusion Criteria:

1. History of any major disease that may interfere with safe engagement in the intervention (especially severe liver or kidney disease, or uncontrolled diabetes).
2. Central nervous system infarct, infection, or focal lesions of clinical significance on MRI scans.

3. Fulfills any contraindication for the use of sirolimus as per the summary of product characteristics, including but not restricted to:

   • Current or planned medication with a strong inhibitor of CYP3A4 or P-gp
   • Current or planned medication with a strong inducer of CYP3A4 or P-gp
   • Other current medications with known serious interaction risks with sirolimus
   • Known allergy or hypersensitivity to sirolimus
4. Significant obesity
5. Untreated and clinically significant hyperlipidemia
6. Treatment with immunosuppressive medications within the last 90 days (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted), or chemotherapeutic agents for malignancy within the last 3 years
7. Major surgery within 3 months prior to the planned start of sirolimus treatment, OR has major surgery planned during the period of the trial.
8. Use of experimental medications for Alzheimer's or any other investigational medication or device within 60 days. Participants who have been involved in a monoclonal antibody study are excluded unless it is known that they were receiving placebo in that trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rapamycin; Sirolimus tablets will be administered orally, 7 mg once per week during 26 weeks	Drug: Sirolimus; 7 mg taken once per week during 26 weeks.; Other Names: Rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cerebral glucose metabolism	Cerebral glucose uptake measured through [18F]FDG positron emission tomography	From baseline to six months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	Safety and tolerability of intermittent sirolimus treatment	From baseline to six months
Change in Cerebrospinal fluid (CSF) concentration of amyloid beta 42	CSF biomarker for Alzheimers disease	From baseline to six months
Change in CSF concentration of phosphorylated tau	CSF biomarker for Alzheimers disease	From baseline to six months
Change in CSF concentration of total tau	CSF biomarker for Alzheimers disease	From baseline to six months
Change in cerebral blood flow	Cerebral blood flow measured with MRI using arterial spin labeling	From baseline to six months
Area under the concentration versus time curve (AUC) of sirolimus	Whole blood measurements of sirolimus concentration.	Tested at one occasion between baseline to six months
Peak Plasma Concentration (Cmax) of sirolimus	Whole blood measurements of sirolimus concentration.	Tested at one occasion between baseline to six months
Trough Plasma Concentration (Cmin) of sirolimus	Whole blood measurements of sirolimus concentration.	Tested at one occasion between baseline to six months
Change in Montreal Cognitive Assessment (MoCA) rating	Cognition assessed using the MoCA rating scale (0-30 points, higher scores indicating better cognitive performance)	From baseline to six months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in composite z-score of neuropsychological tests	Cognition assessed with a composite score of the following tests: Rey Auditory Verbal Learning Test; Rey-Osterrieth Complex Figure; Hagman test; Trail Making Test A + B; Wechsler Adult Intelligence Scale (subtest to assess processing speed/attention). A composite score will be calculated using z-score approach..	From baseline to six months
Change in concentration of neurofilament light in CSF	Neuronal damage assessed using concentraion of neurofilament light in CSF.	From baseline to six months
Change in quotient of albumin concentration in serum and CSF	Blood-brain barrier integrity assessed using quotient of concentration albumin in serum and CSF	From baseline to six months
Change in hand-grip strength	Measured using a hand-grip dynamometer	From baseline to six months
Change in chair stand test	Number of completed chair stands in 30 seconds	From baseline to six months
Change in walking speed	Timed 10-metre dual task walking test	From baseline to six months
Change in ratio of CSF concentration of amyloid beta 42 and 40	CSF biomarker for Alzheimers disease	From baseline to six months

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: Karolinska University Hospital
• Investigators: Principal Investigator: Jonas Svensson, MD, PhD, Karolinska Institutet; Study Director: Pontus Plavén Sigray, PhD, Karolinska Institutet

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2023
• Primary Completion (Actual): December 11, 2024
• Study Completion (Actual): January 17, 2025

Study Registration Dates

• First Submitted: August 15, 2023
• First Submitted That Met QC Criteria: August 30, 2023
• First Posted (Actual): September 1, 2023

Study Record Updates

• Last Update Posted (Actual): July 3, 2025
• Last Update Submitted That Met QC Criteria: June 30, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Sirolimus
• Other Study ID Numbers: 2023-00611-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: We aim to share pseudonymized individual participant data that underlie results in a publication in accordance with institutional regulations.

Drug and device information, study documents

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