Can Alzheimer disease be prevented by amyloid-beta immunotherapy?

Abstract

Alzheimer disease (AD) is the most common form of dementia. The amyloid-beta (Abeta) peptide has become a major therapeutic target in AD on the basis of pathological, biochemical and genetic evidence that supports a role for this molecule in the disease process. Active and passive Abeta immunotherapies have been shown to lower cerebral Abeta levels and improve cognition in animal models of AD. In humans, dosing in the phase II clinical trial of the AN1792 Abeta vaccine was stopped when approximately 6% of the immunized patients developed meningoencephalitis. However, some plaque clearance and modest clinical improvements were observed in patients following immunization. As a result of this study, at least seven passive Abeta immunotherapies are now in clinical trials in patients with mild to moderate AD. Several second-generation active Abeta vaccines are also in early clinical trials. On the basis of preclinical studies and the limited data from clinical trials, Abeta immunotherapy might be most effective in preventing or slowing the progression of AD when patients are immunized before or in the very earliest stages of disease onset. Biomarkers for AD and imaging technology have improved greatly over the past 10 years and, in the future, might be used to identify presymptomatic, at-risk individuals who might benefit from Abeta immunization.

Figure 1

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.

Figure 2

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.