Hyerarchical organic ELectronics sensors for Phenotyping Alzheimer's and Inflammatory Diseases at the Point of Care

Amyloid beta (Aβ) peptides and their isoforms (oligomers, aggregates, protofibrils) are hallmarks of Alzheimer’s Disease (AD) and amyloid-related brain pathologies, such as sporadic cerebral amyloid angiopathy (CAA), and its inflammatory form iCAA that includes CAA-related inflammation- CAA-ri and Aβ-related angiitis-ABRA. In cerebrospinal fluid (CSF) and plasma, abnormal levels of Aβ1-40 and Aβ1-42 reflect these conditions. The immune system expresses antibodies against Aβ and its isoforms. AD patients may, or may not, suffer from CAA and/or iCAA; vice versa CAA/iCAA patients may develop AD. Demonstrating the presence of autoantibodies anti-Aβ isoforms, and correlating them with the levels of inflammatory cytokines, biomarkers from multiomics analysis, and circulating Aβ peptides, will enable clinicians to stratify the patients affected by AD and/or CAA/iCAA. The vision of HELP is a cutting-edge technology for detecting antibodies anti-Ab isoforms based on a novel class of hierarchical electrolyte gated organic transistors (hEGOTs). These devices will integrate Aβ isoforms as recognition elements and transduce the interaction of the isoforms with their antibodies into a mutlparametric electronic response. The measurements will be carried out in patients' CSF and plasma. The breakthrough relies on the judicial selection of isoforms and their anchoring to the gate electrode which will be achieved by controlling the Aβ aggregation on the hEGOT gate electrode surface with our in-house nanotechnology. The profile of auto-antibodies inferred from hEGOT measurements on patients' fluids will allow us to correlate them to clinical biomarkers with the aim to identify inflammatory-prone phenotypes in CAA and AD. We will measure the binding affinity constant of biologial drugs currently on trial against Aβ isoforms, aiming to devise effective personalized treatments. Specific objectives are: 1. To demonstrate EGOT sensors that quantify anti-Aβ1-40/1-42 peptide antibodies n CSF/plasma; 2. To phenotype AD, CAA, iCAA and healthy controls through Aβ load, cytokine levels and biomarkers from multi-omics analyses; 3. To demonstrate hEGOT that quantify antibodies anti-Aβ-isoforms. 4. To explore criteria for personalized anti-amyloid therapy with biological drugs based on the information from hEGOT response.