Multi-modal and multi-organ <i>in vivo</i> imaging to assess geroprotective interventions in humans: results from a pilot trial of rapamycin in Alzheimer’s Disease

Abstract 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); [ 18 F]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, [ 18 F]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 [ 18 F]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.