Changes in the public IgM repertoire and its idiotypic connectivity in Alzheimer's disease and frontotemporal dementia

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are prevalent neurodegenerative disorders. Early diagnosis is challenging due to the lack of definitive biomarkers and reliance on invasive procedures. Immune biomarkers, particularly those reflecting the interaction between the central nervous system (CNS) and the peripheral immune system, have shown promise for non-invasive detection through blood samples. This study investigates the reactivity of serum IgM and IgG from AD and FTD patients against a library of mimotopes representing public IgM reactivities in healthy donors. Serum samples from AD, FTD, and other neurodegenerative dementias (ND) and controls were tested on peptide microarrays. The samples were pooled to mitigate individual variability. The reactivity data were analyzed using graphs to represent the cross-reactivity networks. The analysis revealed distinct reactivity patterns for the studied groups. Public IgM reactivities showed significant correlations with neurodegenerative conditions, with AD and FTD exhibiting loss or gain of specific IgM reactivities. Graph analysis highlighted significant differences between disease and control groups in graph density, clustering, and assortativity parameters. Mimotopes of IgM reactivities lost in dementia, particularly in AD, exhibited significant homology to HCDR3 sequences of human antibodies. Furthermore, clusters of reactivities showed significant distinctions between AD and FTD, with IgG reactivities providing additional differentiation. Several self-proteins related to neurodegeneration proved to have sequences homologous to disease-associated mimotopes. Interestingly, the beta-propeller signature sequence YWTD found in ApoE's receptor LRP1 proved a characteristic epitope for IgG in FTD but not AD. At the same time, the respective public gM mimotope YWTDSSR coincides with a highly conserved sequence in many microorganisms and sequences found in human HCDR3. Thus, the public IgM repertoire, characterized by its broad reactivity and inherent autoreactivity, offers valuable insights into the immunological alterations in neurodegenerative diseases. The study supports the potential of IgM and IgG reactivity profiles as another compartment of non-invasive biomarkers for early diagnosis and differentiating AD and FTD.