Plasma IAPP-Autoantibody Levels in Alzheimer's Disease Patients Are Affected by APOE4 Status

Pancreas-derived islet amyloid polypeptide (IAPP) crosses the blood-brain barrier and co-deposits with amyloid beta (A beta) in brains of type 2 diabetes (T2D) and Alzheimer's disease (AD) patients. Depositions might be related to the circulating IAPP levels, but it warrants further investigation. Autoantibodies recognizing toxic IAPP oligomers (IAPP(O)) but not monomers (IAPP(M)) or fibrils have been found in T2D, but studies on AD are lacking. In this study, we have analyzed plasma from two cohorts and found that levels of neither immunoglobulin (Ig) M, nor IgG or IgA against IAPP(M) or IAPP(O) were altered in AD patients compared with controls. However, our results show significantly lower IAPP(O)-IgA levels in apolipoprotein E (APOE) 4 carriers compared with non-carriers in an allele dose-dependent manner, and the decrease is linked to the AD pathology. Furthermore, plasma IAPP-Ig levels, especially IAPP-IgA, correlated with cognitive decline, C-reactive protein, cerebrospinal fluid A beta and tau, neurofibrillary tangles, and brain IAPP exclusively in APOE4 non-carriers. We speculate that the reduction in IAPP(O)-IgA levels may be caused by increased plasma IAPP(O) levels or masked epitopes in APOE4 carriers and propose that IgA and APOE4 status play a specific role in clearance of circulatory IAPP(O), which may influence the amount of IAPP deposition in the AD brain.

Automated summary

Pancreas-derived islet amyloid polypeptide (IAPP) crosses the blood-brain barrier and co-deposits with amyloid beta (A beta) in brains of type 2 diabetes (T2D) and Alzheimer's disease (AD) patients. Levels of IAPP antibodies were not altered in AD patients compared with controls, but significantly lower IAPP(O)-IgA levels were found in APOE4 carriers, which is linked to the AD pathology. Plasma IAPP-Ig levels, especially IAPP-IgA, correlated with cognitive decline and other AD-related factors in APOE4 non-carriers.