Background Geroprotective interventions, including the mTOR inhibitor rapamycin, slow aging in preclinical models. Translation to humans remains challenging because clinical trials require endpoints detectable within feasible timeframes. Multi-modal in vivo imaging could address this limitation by enabling simultaneous assessment of age-related pathology across multiple organ systems, but its feasibility in clinical trials is uncertain.

Objective To evaluate the feasibility of deploying a multi-modal, multi-organ imaging battery in a geroprotective intervention trial of rapamycin and to collect exploratory efficacy data across multiple domains of age-related pathology.

Methods In a single-center, open-label, single-arm pilot trial, 14 participants with early-stage Alzheimer’s disease (MCI or mild dementia; Montreal Cognitive Assessment ≥18; amyloid-positive) received oral rapamycin 7 mg once weekly for 26 weeks. Participants underwent baseline and end-of-treatment imaging including retinal optical coherence tomography (OCT); [18F]FDG positron emission tomography/computed tomography (PET/CT) of the head, thorax, and lower spine; dentomaxillofacial MRI; and cardiac MRI with stress perfusion and arterial pulse wave velocity. Feasibility outcomes included completion rates and technical or logistical barriers. Exploratory pre-post changes were assessed using paired t-tests.

Results Of the 14 enrolled participants, 13 completed follow-up imaging. Among these, completion was 100% for OCT, [18F]FDG PET/CT, and dentomaxillofacial MRI. Cardiac MRI and pulse wave velocity were completed in 69% (9/13), primarily limited by scanner access during a healthcare worker strike. No imaging-related adverse events occurred. Exploratory analyses showed nominally significant pre-post increases in cardiac output (p=0.017), late diastolic (A-wave) kinetic energy (average: p=0.044; peak: p=0.024), left retinal ganglion cell layer thickness (p=0.044), and optic nerve head [18F]FDG uptake (p=0.040). Bone mineral density showed no significant pre-post changes, while muscle cross-sectional area decreased numerically but not significantly (p=0.058). In exposure-response analyses, higher rapamycin blood concentration was significantly correlated with greater skeletal muscle density (r=0.64, p=0.035) and, albeit not significantly, smaller loss of cross-sectional area (r=−0.53, p=0.097).

Conclusions A multi-modal imaging battery spanning several organ systems was successfully integrated into a clinical trial, with high completion rates for most modalities. Logistical constraints were the primary barriers affecting cardiac measures. These findings inform the design of future randomized trials of geroprotective interventions, where such imaging batteries may help detect changes in age-related pathology over relatively short timeframes.

The authors have declared no competing interest.

NCT06022068

https://link.springer.com/article/10.1186/s12883-024-03596-1

The study was supported by a Longevity Impetus grant from the Norn Group, Ahlen Stiftelsen, Demensfonden, The Swedish Society of Medicine (SLS), Ake Wibergs Stiftelse (M24-0117), Loo and Hans Osterman Stiftelse, Stiftelsen for Alderssjukdomar Karolinska Institutet, Stiftelsen for Gamla Tjanarinnor, Tore Nilssons Stiftelse for Medicinsk Forskning, Magnus Bergvalls stiftelse, Karolinska Institutet Research Grants, and The Swedish Brain Foundation (PD2024-0444-HK-155).

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The study was approved by the Swedish Medical Products Agency (5.1-2023-8283) and the Swedish Ethical Review Authority (2023-03075-02; 2023-00611-01). The study was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice guidelines. Written informed consent was obtained from all participants and a study partner prior to enrolment. The trial was registered at ClinicalTrials.gov (NCT06022068) and EudraCT (2023-000127-36).

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