Vaccines for Alzheimer's disease: how close are we?

Abstract

Alzheimer's disease is a neurodegenerative disorder characterised by a progressive loss of cognitive function. Despite the considerable progress being made, a complete description of the molecular pathology of this disease has yet to be elucidated. The evidence indicates that abnormal processing and extracellular deposition of the longer form of the beta-amyloid (Abeta) peptide (Abeta(1-42), a proteolytic derivative of the amyloid precursor protein [APP]) is implicated in the pathogenesis of Alzheimer's disease. In this respect, recent use of experimental mouse models, in which the mice develop some aspects of Alzheimer's disease in a reproducible fashion, has provided a new opportunity for a multidisciplinary and invasive analysis of mechanisms behind the amyloid pathology and its role in Alzheimer's disease. It has been demonstrated, using a single transgenic mouse model system that overexpresses the human mutated APP gene, that an immunisation against Abeta(1-42) causes a marked reduction in the amyloid burden in the brain. The follow-up research provided more evidence that both active and passive Abeta immunisation also reduces cognitive dysfunction in transgenic mouse models of Alzheimer's disease. Other studies using different approaches - such as secretase, cholesterol and Abeta metalloprotein inhibitors or NSAIDs - but all targeting the abnormal metabolism of Abeta have confirmed in each case that a significant reduction of amyloid plaque burden can be achieved in transgenic mouse models of Alzheimer's disease. This research strongly supports the notion that abnormal Abeta processing is essential to the pathogenesis of Alzheimer's disease and provides a crucial platform for the development and detailed testing of potential treatments in experimental models before each of these approaches can be proposed as a therapy for Alzheimer's disease. Although the first clinical trial of active immunisation with a pre-aggregated synthetic Abeta(42) preparation (AN-1792 vaccine) met with some setbacks and was discontinued after several patients experienced meningoencephalitis, the follow-up analysis of the effect of immunisation against Abeta in humans revealed a powerful effect of vaccination in the clearance of amyloid plaques from the cerebral cortex.