Active vaccination of elderly Alzheimer's disease (AD) patients with fibrillar amyloid-beta peptide (Abeta42), even in the presence of a potent Th1 adjuvant, induced generally low titers of antibodies in a small fraction (approximately 20% responders) of those that received the AN-1792 vaccine. To improve the immunogenicity and reduce the likelihood of inducing adverse autoreactive T-cells specific for Abeta42, we previously tested in wild-type mice an alternative approach for active immunization: an epitope vaccine that selectively initiate B cell responses toward an immunogenic self-epitope of Abeta in the absence of anti-Abeta T cell responses. Here, we describe a second generation epitope vaccine composed of two copies of Abeta(1-11) fused with the promiscuous nonself T cell epitope, PADRE (pan human leukocyte antigen DR-binding peptide) that completely eliminates the autoreactive T cell responses and induces humoral immune responses in amyloid precursor protein transgenic 2576 mice with pre-existing AD-like pathology. Based on the titers of anti-Abeta(1-11) antibody experimental mice were divided into low, moderate and high responders, and for the first time we report a positive correlation between the concentration of anti-Abeta(1-11) antibody and a reduction of insoluble, cerebral Abeta plaques. The reduction of insoluble Abeta deposition was not associated with adverse events, such as CNS T cell or macrophage infiltration or microhemorrhages. Surprisingly, vaccination did not alter the levels of soluble Abeta. Alternatively, early protective immunization before substantial neuropathology, neuronal loss and cognitive deficits have become firmly established may be more beneficial and safer for potential patients, especially if they can be identified in a preclinical stage by the development of antecedent biomarkers of AD.