The pathological hallmarks of Alzheimer's disease (AD) are amyloid-β (Aβ) plaques and Tau-containing neurofibrillary tangles. Although the relationship between neuronal loss and the presence of plaques/tangles is not well understood, the prevailing Aβ hypothesis posits that excessive accumulation of conformers and assemblies of Aβ protein precedes AD-related dementia and neuronal loss. Consequently, most disease-modifying immunotherapy approaches are directed towards modulating the levels of Aβ. The first AD vaccine clinical trial (AN1792) was suspended after the patients developed meningoencephalitis. In spite of the setback, the trial provided insights to refine development second-generation vaccines, which are attempting to resolve the side effects observed in the trial. This article provides an analysis of these efforts.