BACKGROUND: Alzheimer disease (AD) research has focussed mainly on the amyloid beta protein (Aβ). However, many Aβ-and P3-type peptides derived from the amyloid precursor protein (APP) and peptides thought to derive from Aβ 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 Aβ. 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 Aβ-type, P3-type and Aβ-catabolic peptides confound interpretations of immunoreactivity. More than one antibody is required to adequately characterise Aβ. The relationships between anti-Aβ immunoreactivity, neuropathology and proposed APP cleavages are unclear. CONCLUSIONS: We find that the concept of Aβ lacks clarity as a specific entity. Anti-Aβ 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.