Antibodies against many neural antigens are detected in the sera of both patients with Alzheimer's disease (AD) and some healthy individuals. Blood-brain barrier dysfunction could make it possible for brain-reactive autoantibodies to reach the brain, where they can react with amyloid ß peptide (AßP). The origin of these autoreactive antibodies in the blood is unclear. The goals of this study were as follows: (1) to examine the immune reactivity of anti-AßP-42 with 22 neuronal and other associated antigens, some of which are involved in the pathophysiology of AD; (2) to classify antibodies to these 22 different antigens into those that cross-react with AßP-42 and those that do not; (3) to determine whether these antibodies react with BBB proteins, nerve growth factors, and enteric neuronal antigens. Using monoclonal AßP-42 antibody and ELISA methodology, we found that the antibody was highly reactive with Aß protein, tau protein, presenilin, rabaptin-5, β-NGF, BDNF, mTG, and enteric nerve. The same antibody produced equivocal to moderate reactions with glutamate-R, S100B, AQP4, GFAP, MBP, α-synuclein, tTG-2, and tTG-3, and not with the rest. These antibodies were also measured in blood samples from 47 AD patients and 47 controls. IgG antibodies were found to be elevated against AßP-42 and many other antigens in a significant percentage of controls. Overall, the mean OD values were significantly higher against 9/23 tested antigens (p <0.001) in the samples with AD. We were indeed able to classify the detected neuronal antibodies into those that cross-react with AßP-42 and those that do not. Our main finding is that although these antibodies may be harmless in a subgroup of controls, in individuals with compromised BBBs these antibodies that cross-react with AßP-42 can reach the brain, where their cross-reactivity with AßP-42 may contribute to the onset and progression of AD, and perhaps other neurodegenerative disorders.