Background:

We have shown that autoantibodies are ubiquitous in human blood and that specific changes in autoantibody profiles occur that reflect the presence of disease. Autoantibody production is presumably increased in response to the appearance of disease-specific tissue debris in the blood. For AD, our previous studies have exploited this phenomenon and developed panels of autoantibodies that can be used to distinguish healthy control subjects from those with early-stage AD pathology at mild cognitive impairment (MCI), and at more advanced mild-moderate AD with high overall accuracy. Here, we show that early AD pathology can also be linked to the selective depletion of specific brain-reactive autoantibodies, which also has utility for AD detection at both the MCI and mild-moderate AD stages, potentially opening the door to preclinical detection.

Methods:

Sera from over 300 subjects, including 50 MCI (with low CSF Aβ42) and 50 mild-moderate AD subjects, as well as those with Parkinson’s disease, and multiple sclerosis were screened with human protein microarrays containing 9,486 potential antigen targets to identify autoantibodies that are selectively depleted due to the presence of disease. For each disease, 50 autoantibodies with depleted titers relative to controls were identified and evaluated using Random Forest and Receiver Operating Characteristic (ROC) curves for their ability to distinguish disease subjects from age- and sex-matched controls, and from individuals with other neurodegenerative diseases.

Results:

Results demonstrate that detection of depleted autoantibodies in serum can readily differentiate disease subjects from age- and sex-matched controls with high overall accuracy, sensitivity, and specificity. Depletion biomarkers were able to distinguish subjects with early AD pathology at MCI from controls with 90.0% overall accuracy in the Testing Set (sensitivity=88.0%; specificity=92.0%). Comparable accuracies were obtained for identification of subjects with mild-moderate AD, early-stage Parkinson’s disease and multiple sclerosis.

Conclusions:

Results demonstrate that monitoring the disease-linked depletion of brain-reactive autoantibodies in blood has utility for early detection and staging of AD and other neurodegenerative diseases. Since autoantibody depletion may reflect neuropathological events prior to significant neurodegeneration, we hypothesize that depleted autoantibody biomarkers may be particularly useful for preclinical disease detection, perhaps years before the onset of symptoms.