Formation of A beta oligomers and fibrils plays a central role in the pathogenesis of Alzheimer's disease. There are two major forms of A beta in the brain: A beta 42 and A beta 40. A beta 42 is the major component of the amyloid plaques, but the overall abundance of A beta 40 is several times that of A beta 42. In vitro experiments show that A beta 42 and A beta 40 affect each other's aggregation. In mouse models of Alzheimer's disease, overexpression of A beta 40 has been shown to reduce the plaque pathology, suggesting that A beta 42 and A beta 40 also interact in vivo. Here we address the question of whether A beta 42 and A beta 40 interact with each other in the formation of oligomers using electron paramagnetic resonance (EPR) spectroscopy. When the A beta 42 oligomers were formed using only spin-labeled A beta 42, the dipolar interaction between spin labels that are within 20 A range broadened the EPR spectrum and reduced its amplitude. Oligomers formed with a mixture of spin-labeled A beta 42 and wild-type A beta 42 gave an EPR spectrum with higher amplitude due to weakened spin-spin interactions, suggesting molecular mixing of labeled and wild-type A beta 42. When spin-labeled A beta 42 and wild-type A beta 40 were mixed to form oligomers, the resulting EPR spectrum also showed reduced amplitude, suggesting that wild-type A beta 40 can also form oligomers with spin-labeled A beta 42. Therefore, our results suggest that A beta 42 and A beta 40 form mixed oligomers with direct molecular interactions. Our results point to the importance of investigating A beta 42-A beta 40 interactions in the brain for a complete understanding of Alzheimer's pathogenesis and therapeutic interventions. (C) 2020 Elsevier Inc. All rights reserved.