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  3. Evaluating the effect of rapamycin treatment in Alzheimer's disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol

Evaluating the effect of rapamycin treatment in Alzheimer's disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol

  • BMC Neurol. 2024 Apr 4;24(1):111. doi: 10.1186/s12883-024-03596-1.
Jonas E Svensson 1 2,  Martin Bolin 1,  Daniel Thor 3 4,  Pete A Williams 5,  Rune Brautaset 5,  Marcus Carlsson 6,  Peder Sörensson 7,  David Marlevi 6 8,  Rubens Spin-Neto 9,  Monika Probst 10,  Göran Hagman 2 11,  Anton Forsberg Morén 1,  Miia Kivipelto 2 11 12 13,  Pontus Plavén-Sigray 14 15
Affiliations

Affiliations

  • 1 Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
  • 2 Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden.
  • 3 Department of Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden.
  • 4 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
  • 5 Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
  • 6 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • 7 Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
  • 8 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 9 Department of Dentistry and Oral Health, Section for Oral Radiology, Aarhus University, Aarhus C, Denmark.
  • 10 Department of Diagnostic and Interventional Neuroradiology, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
  • 11 Department of Neurobiology, Care Sciences, and Society, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
  • 12 Ageing Epidemiology Research Unit (AGE), School of Public Health, Faculty of Medicine, Imperial College London, London, UK.
  • 13 Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
  • 14 Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden. [email protected].
  • 15 Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. [email protected].
PMID: 38575854 DOI: 10.1186/s12883-024-03596-1
Abstract

Background: Rapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, and preclinical data demonstrate that it is a promising candidate for a general gero- and neuroprotective treatment in humans. Results from mouse models of Alzheimer's disease have shown beneficial effects of rapamycin, including preventing or reversing cognitive deficits, reducing amyloid oligomers and tauopathies and normalizing synaptic plasticity and cerebral glucose uptake. The "Evaluating Rapamycin Treatment in Alzheimer's Disease using Positron Emission Tomography" (ERAP) trial aims to test if these results translate to humans through evaluating the change in cerebral glucose uptake following six months of rapamycin treatment in participants with early-stage Alzheimer's disease.

Methods: ERAP is a six-month-long, single-arm, open-label, phase IIa biomarker-driven study evaluating if the drug rapamycin can be repurposed to treat Alzheimer's disease. Fifteen patients will be included and treated with a weekly dose of 7 mg rapamycin for six months. The primary endpoint will be change in cerebral glucose uptake, measured using [18F]FDG positron emission tomography. Secondary endpoints include changes in cognitive measures, markers in cerebrospinal fluid as well as cerebral blood flow measured using magnetic resonance imaging. As exploratory outcomes, the study will assess change in multiple age-related pathological processes, such as periodontal inflammation, retinal degeneration, bone mineral density loss, atherosclerosis and decreased cardiac function.

Discussion: The ERAP study is a clinical trial using in vivo imaging biomarkers to assess the repurposing of rapamycin for the treatment of Alzheimer's disease. If successful, the study would provide a strong rationale for large-scale evaluation of mTOR-inhibitors as a potential disease-modifying treatment in Alzheimer's disease.

Trial registration: ClinicalTrials.gov ID NCT06022068, date of registration 2023-08-30.

Keywords

Aging; Alzheimer’s disease; CT; Clinical trial; Geroprotection; MRI; OCT; PET; Rapamycin; Sirolimus.

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