Altered anti-TDP-43 and global immunoglobulin profiles before and after ALS diagnosis

Humoral immune changes in amyotrophic lateral sclerosis (ALS) remain incompletely defined. We examined whether serum anti-TDP-43 and global immunoglobulin profiles differ before and after ALS diagnosis. Serum from 59 ALS patients contributing 108 samples and 103 normal controls (NC) was analyzed. ALS samples were classified as pALS before diagnosis and cALS at or after diagnosis. We measured TDP-43 competition binding, anti-TDP-43 IgG subclasses, anti-TDP-43 total IgG, anti-TDP-43 IgM, and global immunoglobulins. Patient-level cross-sectional, paired pALS-cALS, random-intercept mixed-effects, exploratory PCA, and patient-level ROC analyses were performed. TDP-43 competition binding did not show robust group differences or significant within-patient longitudinal change after false discovery rate correction. Anti-TDP-43 IgG1 was lower in pALS and cALS than in NC, while anti-TDP-43 total IgG was higher in both ALS groups. Anti-TDP-43 total IgG increased within ALS patients over time (beta = 0.050/year, 95% CI 0.026 to 0.073, q = 0.00023). Global immunoglobulin analyses showed lower global IgG2 and IgG3 and higher global IgG4 and IgM in ALS samples. Exploratory PCA showed partially overlapping profiles; PC1 and PC2 explained 18.7% and 17.7% of variance. Patient-level ROC analyses identified anti-TDP-43 IgG1, anti-TDP-43 total IgG, global IgG4, and global IgM as the strongest exploratory classifiers. Serum antibody profiles differed in ALS samples collected before and after diagnosis compared with NC, supporting altered humoral immunity.