Alzheimer's disease (AD) is characterized by the deposition of amyloid plaques, loss of neurons, neuritic degeneration, accumulation of fibrillary tangles in neurons, and a progressive loss of cognitive function. Amyloid-β peptide (Aβ) appears to play a pivotal role in the development of AD. Clearance of Aβ from the brain represents an important therapeutic strategy for prevention and treatment of AD. Immunotherapy targeting Aβ is effective to remove the peptide from the brain. However, it is associated with detrimental adverse effects, such as autoimmune meningoencephalitis and microhemorrhage. These are presumably the results of brain infiltration of provoked autoimmune T lymphocytes in response to Aβ vaccination and release of proinflammatory cytokines from microglia activated by the immune complex of Aβ and antibodies. An improvement of the safety of the immunotherapy is a major goal of the immunotherapy study. Here, we review the mechanisms involved in modified immunological strategies, as well as their adverse effects. We discuss the following: the development of B epitope vaccines to avoid activation of autoimmune T lymphocytes; DNA vaccines containing appropriate immunostimulatory and immunomodulatory sequences to induce the desired humoral immune responses; antibody modifications to avoid activation of microglia and subsequent release of proinflammatory cytokines; single chain antibodybased gene therapy; immunotherapy targeting Aβ oligomers; modulation of antibody delivery approach and dose; and application of autoantibodies against Aβ. These ultimately represent future directions of therapeutic approaches toward safer and effective Aβ clearance.