Integrative analysis reveals the autoantibodyome neuroimmune signature of neurodegeneration

Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), are complex conditions driven by systemic dysregulation that transcends the central nervous system. An integrative systems immunology framework was applied to characterize the neuroimmune "autoantibodyome" across neurodegeneration through an individual participant data meta-analysis of five protein microarray datasets, comprising 596 samples from patients with AD, PD, or MS and healthy controls. We mapped differentially reactive autoantibodies stratified by their targets, unveiling shared features among diseases, such as blood-brain barrier impairment and amplified pro-inflammatory activation, alongside disease-specific perturbations in neuroimmune processes, including short-term memory (AD), skeletal muscle contraction (PD), and pain perception (MS). We identified convergent dysregulation of various autoantibodies targeting diverse synaptic transmission pathways, including gamma-aminobutyric acid (GABA)ergic and glutamatergic signaling. These results indicate the potential of the autoantibodyome to interact with and report on central alterations, suggesting that neurodegeneration may be better understood as a systemic dyshomeostasis.