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

TY - JOUR

T1 - Plasma IAPP-Autoantibody Levels in Alzheimer's Disease Patients Are Affected by APOE4 Status

AU - Pocevičiūtė, Dovilė

AU - Roth, Bodil

AU - Schultz, Nina

AU - Nuñez-Diaz, Cristina

AU - Janelidze, Shorena

AU - Huitinga, I.

AU - Olofsson, Anders

AU - Hansson, Oskar

AU - Wennström, Malin

PY - 2023/2/14

Y1 - 2023/2/14

N2 - Pancreas-derived islet amyloid polypeptide (IAPP) crosses the blood-brain barrier and co-deposits with amyloid beta (Aβ) 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 (IAPPO) but not monomers (IAPPM) 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 IAPPM or IAPPO were altered in AD patients compared with controls. However, our results show significantly lower IAPPO-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 Aβ and tau, neurofibrillary tangles, and brain IAPP exclusively in APOE4 non-carriers. We speculate that the reduction in IAPPO-IgA levels may be caused by increased plasma IAPPO levels or masked epitopes in APOE4 carriers and propose that IgA and APOE4 status play a specific role in clearance of circulatory IAPPO, which may influence the amount of IAPP deposition in the AD brain.

AB - Pancreas-derived islet amyloid polypeptide (IAPP) crosses the blood-brain barrier and co-deposits with amyloid beta (Aβ) 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 (IAPPO) but not monomers (IAPPM) 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 IAPPM or IAPPO were altered in AD patients compared with controls. However, our results show significantly lower IAPPO-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 Aβ and tau, neurofibrillary tangles, and brain IAPP exclusively in APOE4 non-carriers. We speculate that the reduction in IAPPO-IgA levels may be caused by increased plasma IAPPO levels or masked epitopes in APOE4 carriers and propose that IgA and APOE4 status play a specific role in clearance of circulatory IAPPO, which may influence the amount of IAPP deposition in the AD brain.

U2 - 10.3390/ijms24043776

DO - 10.3390/ijms24043776

M3 - Article

C2 - 36835187

SN - 1661-6596

VL - 24

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 4

M1 - 3776

ER -