New
biomarkers of
Alzheimer's disease (AD) with a diagnostic value in preclinical and
prodromal stages are urgently needed. AD-related serum
autoantibodies are potential candidate
biomarkers. Here, we aimed at identifying AD-related serum
autoantibodies using
protein microarrays and mass spectrometry-based methods. To this end, an untargeted complementary screening using high-density (42,100
antigens) and low-density (384
antigens) planar
protein-
epitope signature tag (PrEST) arrays and an immunoprecipitation protocol coupled to mass spectrometry analysis were used for serum
autoantibody profiling. From the untargeted screening phase, 377
antigens corresponding to 338
proteins were selected for validation. Out of them, IVD, CYFIP1, and ADD2 seroreactivity was validated using 128 sera from AD patients and controls by PrEST-
suspension bead arrays, and ELISA or luminescence
Halotag-based bead immunoassay using full-length
recombinant proteins. Importantly, IVD, CYFIP1, and ADD2 showed in combination a noticeable AD diagnostic ability. Moreover, IVD
protein abundance in the prefrontal cortex was significantly two-fold higher in AD patients than in controls by western blot and immunohistochemistry, whereas CYFIP1 and ADD2 were significantly down-regulated in AD patients. The panel of AD-related
autoantigens identified by a comprehensive multiomics approach may provide new insights of the disease and should help in the blood-based diagnosis of
Alzheimer's disease. Mass spectrometry raw data are available in the ProteomeXchange database with the access number PXD028392.