Efficacy of antibody-based therapies to treat Alzheimer's disease: just a matter of timing?

Abstract

A pharmaceutical intervention that has received great attention in recent years for treating Alzheimer's disease (AD) is the use of antibodies targeting amyloid beta (Aβ) in the brain, as the formation of Aβ plaques is considered as being the driving force for the development and progression of AD. Recently, a Phase III trial in patients with mild-to-moderate AD has provided ambivalent evidence for the efficacy of this intervention. In this trial, the intravenous administration of bapineuzumab, a monoclonal antibody targeting Aβ in the brain, for 78weeks led to a reduction of cerebrospinal fluid levels of phosphorylated tau and evidence for lower Aβ accumulation in the brain of AD patients who carried APOE ε4. However, this treatment did not improve clinical outcomes (e.g. the rate of cognitive decline) in these patients. Similar null results with respect to the rate of cognitive decline were found in a separate Phase III clinical trial after treatment with solanezumab. Based on these findings, one conclusion could be that antibodies targeting Aβ in the brain may unfold their highest efficacy when given before the development of clinical AD symptoms, i.e. during a period where neurodegeneration but not cognitive loss represents the major pathology. Another conclusion could be that antibody-based pharmaceutical interventions may fail to slow the progress of cognitive loss in patients who have AD because of their solely pharmaceutical therapeutic approach. Leisure activities that require patients' mental and physical abilities (e.g. exercise) are associated with a reduced risk of developing dementia. In the same manner, they may help to curb the progress of this devastating disease. Thus, combining the use of antibodies targeting Aβ with therapeutic strategies that require patients' mental and physical abilities might help tackle the neurodegenerative dynamics and cognitive loss both in patients with AD, and its prodromal state, mild cognitive impairment.

Keywords: Alzheimer's disease; Antibody-based therapy; Cognitive decline; Lifestyle factors; Phase III clinical trials.