Do anti-amyloid beta protein antibody cross reactivities confound Alzheimer disease research?

Background: Alzheimer disease (AD) research has focussed mainly on the amyloid beta protein (A beta). However, many A beta-and P3-type peptides derived from the amyloid precursor protein (APP) and peptides thought to derive from A beta catabolism share sequence homology. Additionally, conformations can change dependent on aggregation state and solubility leading to significant uncertainty relating to interpretations of immunoreactivity with antibodies raised against A beta. We review evidence relating to the reactivities of commonly used antibodies including 6F3D, 6E10 and 4G8 and evaluate their reactivity profiles with respect to AD diagnosis and research. Results: Antibody cross-reactivities between A beta-type, P3-type and A beta-catabolic peptides confound interpretations of immunoreactivity. More than one antibody is required to adequately characterise A beta. The relationships between anti-A beta immunoreactivity, neuropathology and proposed APP cleavages are unclear. Conclusions: We find that the concept of A beta lacks clarity as a specific entity. Anti-A beta antibody cross-reactivities lead to significant uncertainty in our understanding of the APP proteolytic system and its role in AD with profound implications for current research and therapeutic strategies.