Evaluating the effect of rapamycin treatment in Alzheimer's Disease and aging using in vivo imaging: the phase IIa ERAP trial protocol.

Background Rapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, and pre-clinical data demonstrate that it is a promising candidate for a general gero- and neuroprotective treatments 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 will be change 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. Conclusion 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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT06022068 ### Funding Statement The study is funded by a Longevity Impetus grant from the Norn Group, Åhlén Stiftelsen, Demensfonden, The Swedish Society of Medicine (SLS), Loo and Hans Osterman Stiftelse, Stiftelsen för Ålderssjukdomar Karolinska Institutet, Stiftelsen för Gamla Tjänarinnor, Tore Nilssons Stiftelse för Medicinsk Forskning, Stiftelsen Stockholms Sjukhem, Region Stockholm (ALF grant) and KI CIMED. None of the funding bodies had any role in the design of the study and in writing the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Swedish Ethical Review Authority (Etikprövningsmyndigheten, number: 2023-03075-02 and 2023-00611-01) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data collected as part of the trial will be shared in accordance with institutional regulations.