Active and passive immunization approaches. a | Vaccination (active immunization) activates the body’s immune system to produce antigen-specific antibodies. In AD, full-length Aβ or a fragment of Aβ conjugated to a foreign T cell epitope carrier protein can be used as an antigen, which is delivered into the body alongside an immune system booster (adjuvant). The humoral immune response is generated when APCs, which take up and process the antigen, present T cell epitopes to naive T_H lymphocytes, activating the latter (first signal). Binding of co-stimulatory molecules on the surfaces of APCs and T cells provides a secondary signal that enhances T cell activation. Meanwhile, the soluble antigen binds to B cell receptors, via the B cell epitope, and this antigen is presented to activated T cells to help the B cell make antibodies against the antigen. Activated T cells also produce cellular immune responses. A T_H1 cellular immune response leads to the release of pro-inflammatory cytokines, whereas a T_H2 response causes release of anti-inflammatory cytokines. b | Passive immunization bypasses the need for the body to mount an immune response to produce antigen-specific antibodies. In both active and passive Aβ immunization, anti-Aβ antibodies bind Aβ, targeting the peptide for clearance. Abbreviations: Aβ, amyloid-β; APC, antigen presenting cell; T_H, T helper.

Neuropathological findings in an AN1792-immunized patient with Alzheimer disease. A 71 year-old male patient with a 10 year history of dementia was administered three doses of AN1792. He died a year later due to failure to thrive, but did not develop meningoencephalitis. a | Gross morphology of the brain showed preservation of the limbic structures and cortical ribbon. b | In the frontal cortex, although amyloid-β immunoreactive macrophages were abundant, no amyloid plaques were detected. c | Cortical vessels exhibited persistent amyloidosis despite removal of the surrounding amyloid plaques. d | CD4-positive T cells (indicated by brown staining) were frequently located around blood vessels. e | In areas where amyloid was removed, the neuritic network (labeled with an anti-neurofilament antibody) appeared preserved.