Nowhere to run, nowhere to hide ‐ targeting the immune system in AD with multimodal plasma therapeutics

Abstract

AbstractBackgroundAge‐related diseases, especially Alzheimer’s Disease (AD), have multifaceted nature because of the different factors and pathways contributing to these diseases. Multi‐modal plasma therapies have the potential to impact multiple pathways and modulate different mechanisms of diseases in a safe and versatile way. Here we discuss insights from deep plasma proteomics profiling in patients from the GRF6019 and AMBAR clinical trials in which multi‐modal plasma therapeutics were used and limited cognitive decline was observed.MethodThe GRF6019 phase 2 trials were based on the infusion of a complex plasma fraction while the AMBAR phase 2b/3 trial used plasma exchange and albumin replacement (PE‐Alb). Patients in these trials were mild‐to‐moderate AD and 1143 plasma samples were analyzed using the SomaScan platform. The trajectories of 7k proteins were analyzed using classic and new machine learning techniques.ResultGRF6019 infusion resulted in an acute and broad impact on the plasma proteome but the detectable long‐term effects on molecular level were minimal. Pathways analysis of protein trajectories pointed out to the immune system, ECM remodeling but also brain specific biological processes linked to neurons and axon guidance, suggesting that various biological pathways were significantly modulated (q<0.05). PE‐Alb treatment also induced an acute effect on several hundreds of proteins (461 proteins with log2FC←1 & q<0.05) but some proteomics changes lasted for weeks after the end of the intensive period (25 proteins with q<0.05). A significant part of these changes (19% of acute and 56% of lasting response proteins) were related to immune and inflammatory‐related pathways. In addition, several individual proteins from the immune pathway were associated with improvement of CDR‐SB or ADCS‐CGIC at the end of the AMBAR trial suggesting that multiple parts of the immune system might need to be targeted to slow‐down AD progression.ConclusionAD has multifaceted nature and plasma therapeutics have proven safety, efficacy, and versatility. The proteomics results from these trials shed the light on the underlying mode of action of multi‐modal plasma‐derived therapies and demonstrate that they can modulate multiple pathways relevant to AD, with a strong effect on the immune and inflammatory responses which may contribute to slowing down AD progression.