Introduction: Alzheimer's disease (AD) vaccination is one of the last therapeutic options after two decades of stagnation in terms of drug development. About 140 (85%) immunization procedures against A beta deposition and 25 (15%) against Tau have been reported, but no Food and Drug Administration approval of any AD vaccine has been achieved. This might be attributed to deficient pathogenic targets, inappropriate models, defective immunotherapeutic procedures, and inadequate clinical trial design. Areas covered: The issues covered include the following: AD pathogenic mechanisms, rationale for active and passive immunization, vaccine targets, anti-A beta/Tau vaccines, vaccine technologies, animal models, and clinical trials. Expert opinion: A vaccine against AD is technically feasible; however, important methodological aspects should be changed for a tentative clinical success, including (i) the development of multitarget AD immunotherapies; (ii) the optimization of antibody titers and epitopes; (iii) the pharmacogenetic/pharmacoepigenetic validation of the immunization procedure; (iv) the prophylactic treatment of genetically stratified patients at a pre-symptomatic stage; and (v) the definition of primary endpoints in prevention, based on objective/multifactorial biomarkers. Even with exquisite protocols, a successful vaccine would be potentially useful in at most 20-30% of defined cases, according to the genetic, epigenetic, and pharmacogenetic background of AD patients.
