Autoantibody profiles in Alzheimer<acute accent>s, Parkinson<acute accent>s, and dementia with Lewy bodies: altered IgG affinity and IgG/IgM/IgA responses to alpha-synuclein, amyloid-beta, and tau in disease-specific pathological patterns

BackgroundAlzheimer's disease (AD) and Parkinson's disease (PD) are leading neurodegenerative disorders marked by protein aggregation, with AD featuring amyloid-beta (A beta) and tau proteins, and PD alpha-synuclein (alpha Syn). Dementia with Lewy bodies (DLB) often presents with a mix of these pathologies. This study explores naturally occurring autoantibodies (nAbs), including Immunoglobulin (Ig)G, IgM, and IgA, which target alpha Syn, A beta and tau to maintain homeostasis and were previously found altered in AD and PD patients, among others.Main textWe extended this investigation across AD, PD and DLB patients investigating both the affinities of IgGs and levels of IgGs, IgMs and IgAs towards alpha Syn, A beta and tau utilizing chemiluminescence assays. We confirmed that AD and PD patients exhibited lower levels of high-affinity anti-A beta and anti-alpha Syn IgGs, respectively, than healthy controls. AD patients also showed diminished levels of high-affinity anti-alpha Syn IgGs, while anti-tau IgG affinities did not differ significantly across groups. However, DLB patients exhibited increased anti-alpha Syn IgG but decreased anti-alpha Syn IgM levels compared to controls and PD patients, with AD patients showing a similar pattern. Interestingly, AD patients had higher anti-A beta IgG but lower anti-A beta IgA levels than DLB patients. DLB patients had reduced anti-A beta IgM levels compared to controls, and anti-tau IgG levels were lower in AD than PD patients, who had reduced anti-tau IgM levels compared to controls. AD patients uniquely showed higher anti-tau IgA levels. Significant correlations were observed between clinical measures and nAbs, with negative correlations between anti-alpha Syn IgG affinity and levels in DLB patients and a positive correlation with anti-alpha Syn IgA levels in PD patients. Disease-specific changes in nAb levels and affinity correlations were identified, highlighting altered immune responses.ConclusionThis study reveals distinctive nAb profiles in AD, DLB, and PD, pinpointing specific immune deficiencies against pathological proteins. These insights into the autoreactive immune system's role in neurodegeneration suggest nAbs as potential markers for vulnerability to protein aggregation, offering new avenues for understanding and possibly diagnosing these conditions.