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

doi:10.1186/s12883-024-03596-1

. 2024 Apr 4;24(1):111.

doi: 10.1186/s12883-024-03596-1.

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

Jonas E Svensson^{1

2}, Martin Bolin¹, Daniel Thor^{3

4}, Pete A Williams⁵, Rune Brautaset⁵, Marcus Carlsson⁶, Peder Sörensson⁷, David Marlevi^{6

8}, Rubens Spin-Neto⁹, Monika Probst¹⁰, Göran Hagman^{2

11}, Anton Forsberg Morén¹, Miia Kivipelto^{2

11

12

13}, Pontus Plavén-Sigray^{14

15}

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. pontus.plaven-sigray@ki.se.
¹⁵ Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. pontus.plaven-sigray@ki.se.

PMID: 38575854
PMCID: PMC10993488
DOI: 10.1186/s12883-024-03596-1

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

Jonas E Svensson et al. BMC Neurol. 2024.

. 2024 Apr 4;24(1):111.

doi: 10.1186/s12883-024-03596-1.

Authors

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. pontus.plaven-sigray@ki.se.
¹⁵ Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. pontus.plaven-sigray@ki.se.

PMID: 38575854
PMCID: PMC10993488
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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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
Study timeline for each participant

See this image and copyright information in PMC

Cited by

Pharmacological mTOR inhibitors in ameliorating Alzheimer's disease: current review and perspectives.
Xie PL, Zheng MY, Han R, Chen WX, Mao JH. Xie PL, et al. Front Pharmacol. 2024 May 30;15:1366061. doi: 10.3389/fphar.2024.1366061. eCollection 2024. Front Pharmacol. 2024. PMID: 38873415 Free PMC article. Review.

References

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[1] Ackley SF, Zimmerman SC, Brenowitz WD, Tchetgen Tchetgen EJ, Gold AL, Manly JJ, et al. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021;372:n156. doi: 10.1136/bmj.n156. - DOI - PMC - PubMed

[2] Ackley SF, Zimmerman SC, Brenowitz WD, Tchetgen Tchetgen EJ, Gold AL, Manly JJ, et al. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021;372:n156. doi: 10.1136/bmj.n156. - DOI - PMC - PubMed

[3] Thambisetty M, Howard R. Lecanemab trial in AD brings hope but requires greater clarity. Nat Rev Neurol. 2023;19(3):132–133. doi: 10.1038/s41582-022-00768-w. - DOI - PubMed

[4] Thambisetty M, Howard R. Lecanemab trial in AD brings hope but requires greater clarity. Nat Rev Neurol. 2023;19(3):132–133. doi: 10.1038/s41582-022-00768-w. - DOI - PubMed

[5] Prince MJ, Wimo A, Guerchet MM, Ali GC, Wu YT, Prina M. World Alzheimer report 2015 - The global impact of dementia. An analysis of prevalence, incidence, cost and trends. London: Alzheimer’s Disease International; 2015.

[6] Prince MJ, Wimo A, Guerchet MM, Ali GC, Wu YT, Prina M. World Alzheimer report 2015 - The global impact of dementia. An analysis of prevalence, incidence, cost and trends. London: Alzheimer’s Disease International; 2015.

[7] Qiu C, Kivipelto M, von Strauss E. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci. 2009;11(2):111–128. doi: 10.31887/DCNS.2009.11.2/cqiu. - DOI - PMC - PubMed

[8] Qiu C, Kivipelto M, von Strauss E. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci. 2009;11(2):111–128. doi: 10.31887/DCNS.2009.11.2/cqiu. - DOI - PMC - PubMed

[9] Nadon NL, Strong R, Miller RA, Harrison DE. NIA interventions testing program: investigating putative aging intervention agents in a genetically heterogeneous mouse model. EBioMedicine. 2017;21:3–4. doi: 10.1016/j.ebiom.2016.11.038. - DOI - PMC - PubMed

[10] Nadon NL, Strong R, Miller RA, Harrison DE. NIA interventions testing program: investigating putative aging intervention agents in a genetically heterogeneous mouse model. EBioMedicine. 2017;21:3–4. doi: 10.1016/j.ebiom.2016.11.038. - DOI - PMC - PubMed

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

Affiliations

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

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