Pre-clinical and clinical data suggest that the development of a safe and 
effective anti-amyloid-beta (Abeta) immunotherapy for Alzheimer's disease (AD) 
will require therapeutic levels of anti-Abeta antibodies, while avoiding 
proinflammatory adjuvants and autoreactive T cells which may increase the 
incidence of adverse events in the elderly population targeted to receive 
immunotherapy. The first active immunization clinical trial with AN1792 in AD 
patients was halted when a subset of patients developed meningoencephalitis. The 
first passive immunotherapy trial with bapineuzumab, a humanized monoclonal 
antibody against the end terminus of Abeta, also encountered some dose dependent 
adverse events during the Phase II portion of the study, vasogenic edema in 12 
cases, which were significantly over represented in ApoE4 carriers. The proposed 
remedy is to treat future patients with lower doses, particularly in the ApoE4 
carriers. Currently there are at least five ongoing anti-Abeta immunotherapy 
clinical trials. Three of the clinical trials use humanized monoclonal 
antibodies, which are expensive and require repeated dosing to maintain 
therapeutic levels of the antibodies in the patient. However in the event of an 
adverse response to the passive therapy antibody delivery can simply be halted, 
which may provide a resolution to the problem. Because at this point we cannot 
readily identify individuals in the preclinical or prodromal stages of AD 
pathogenesis, passive immunotherapy is reserved for those that already have 
clinical symptoms. Unfortunately those individuals have by that point 
accumulated substantial neuropathology in affected regions of the brain. 
Moreover, if Abeta pathology drives tau pathology as reported in several 
transgenic animal models, and once established if tau pathology can become self 
propagating, then early intervention with anti-Abeta immunotherapy may be 
critical for favorable clinical outcomes. On the other hand, active immunization 
has several significant advantages, including lower cost and the typical 
immunization protocol should be much less intrusive to the patient relative to 
passive therapy, in the advent of Abeta-antibody immune complex-induced adverse 
events the patients will have to receive immuno-supperssive therapy for an 
extended period until the anti Abeta antibody levels drop naturally as the 
effects of the vaccine decays over time. Obviously, improvements in vaccine 
design are needed to improve both the safety, as well as the efficacy of 
anti-Abeta immunotherapy. The focus of this review is on the advantages of DNA 
vaccination for anti-Abeta immunotherapy, and the major hurdles, such as 
immunosenescence, selection of appropriate molecular adjuvants, universal T cell 
epitopes, and possibly a polyepitope design based on utilizing existing memory T 
cells in the general population that were generated in response to childhood or 
seasonal vaccines, as well as various infections. Ultimately, we believe that 
the further refinement of our AD DNA epitope vaccines, possibly combined with a 
prime boost regime will facilitate translation to human clinical trials in 
either very early AD, or preferably in preclinical stage individuals identified 
by validated AD biomarkers.