Identification of novel candidate autoantibodies in Alzheimer's disease.

BACKGROUND AND PURPOSE: Accumulated failures in Alzheimer's disease (AD) clinical trials have highlighted an urgent need to identify additional biomarkers involved in AD. Recently, mounting evidence reported that autoantibodies are ubiquitous in human sera. However, whether autoantibodies are upregulated in amyloid-tau biomarker confirmed AD is unknown. METHODS: Forty subjects with mild dementia (CDR=1) were stratified into AD (N=16) and non-AD (N=24) groups according to their CSF levels of tau and Aβ42 . Their sera were collected and analyzed using a microarray containing >1600 potential human autoantigens. Autoantibodies that were present exclusively in the AD group were identified and selected using the penetrance-based fold change method using the following criteria: Penetrance Fold Change(AD) ≥2, Frequency(AD) ≥15%, Frequency(non-AD) =0%. RESULTS: All controls and samples passed the QC criteria and were further used for biomarker analysis. Six autoantibodies with elevated responses to the following autoantigens were found exclusively in the AD group: NAP1L3 (31.3%, 5/16 subjects), MAP4, PANK3, PIK3R1, PTP4A1, and SOX15 (all 18.8%, 3/16 subjects). CONCLUSION: While some identified autoantigens are linked to AD and cognitive dysfunction, the increased autoantibody levels have not been reported in AD. Autoantibodies may provide deeper insights into the pathogenesis of AD and serve as diagnostic biomarkers; their corresponding antigens can be further studied to assess their potential as therapeutic targets.