Deep plasma proteomics reveal age‐related molecular pathways modulated by GRF6019 treatment in Alzheimer’s disease patients

Abstract

AbstractBackgroundBlood has been widely investigated to discover biomarkers and gain insights into the biology of aging and age‐related diseases. Its protein composition provides information about complex biological processes, as proteins are often direct regulators of cellular pathways. Using recent methodological developments allowing the measurement of thousands of proteins with very high sensitivity and specificity, we sought to understand comprehensive proteomic changes in two AD clinical trials.MethodPhase 2 clinical trials (GRF6019‐201 n=40 and GRF6019‐202 n=26) testing the safety, tolerability, and feasibility of repeated infusions of the plasma fraction GRF6019 in Alzheimer's disease (AD) were used as the source to measure more than 7000 proteins in plasma using the SOMAscan and Olink assays. To evaluate the relevance of the proteomics changes induced by GRF6019, we compared these changes to those observed in a healthy aging cohort (∼5000 proteins measured in 370 subjects).ResultStandard statistical analysis at the protein levels lacked power due to the small sample size in phase 2 clinical trials. By analyzing trajectories of groups of proteins, clinical proteomics revealed multiple clusters of proteins responding to GRF6019. Remarkably, several pathways modulated by GRF6019 were particularly relevant for the biology of aging and AD – including the complement/coagulation cascades and neuronal pathways (q<0.05).ConclusionAltogether, our results suggest that the treatment of AD patients with a complex plasma fraction modulates biological pathways that are relevant to aging and AD. Our results establish deep proteomics as a powerful tool to study human response to treatment in clinical trials.