Immunotherapy as treatment for Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized pathologically by the deposition of β-amyloid (Aβ)-containing extracellular neuritic plaques, intracellular neurofibrillary tangles and neuronal loss. Much evidence supports the hypothesis that Aβ peptide aggregation contributes to AD pathogenesis, however, currently approved therapeutic treatments do nothing to stop or reverse Aβ deposition. The success of active and passive anti-Aβ immunotherapies in both preventing and clearing parenchymal amyloid in transgenic mouse models led to the initiation of an active anti-Aβ vaccination (AN1792) trial in human patients with mild-to-moderate AD, but was prematurely halted when 6% of inoculated patients developed aseptic meningoencephalitis. Autopsy results from the brains of four individuals treated with AN1792 revealed decreased plaque burden in select brain areas, as well as T-cell lymphocytes in three of the patients. Furthermore, antibody responders showed some improvement in memory task measures. These findings indicated that anti-Aβ therapy might still be a viable option for the treatment of AD, if potentially harmful proinflammatory processes can be avoided. Over the past 6 years, this target has led to the development of novel experimental immunization strategies, including selective Aβ epitope targeting, antibody and adjuvant modifications, as well as alternative routes and mechanisms of vaccine delivery, to generate anti-Aβ antibodies that selectively target and remove specific Aβ species without evoking autoimmunity. Results from the passive vaccination AD clinical trials that are currently underway will provide invaluable information about both the effectiveness of newly improved anti-Aβ vaccines in clinical treatment, as well as the role of the Aβ peptide in the pathogenesis of the disease.

Keywords::

• Alzheimer’s disease
• animal models
• clinical trials
• vaccination

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.