Moving beyond anti-amyloid therapy for the prevention and treatment of Alzheimer's disease

Abstract

Background: High-profile Phase 3 clinical trials of bapineuzumab and solanezumab, antibodies targeted at amyloid-beta (Aβ) removal, have failed to meet their primary endpoints. Neither drug improves clinical outcomes in patients with late onset AD, joining a long list of unsuccessful attempts to treat AD with anti-amyloid therapies.

Discussion: These therapies are based on the assumption that Aβ accumulation is the primary pathogenic trigger of AD. Current evidence suggests that Aβ may actually accumulate as part of an adaptive response to long-term chronic brain stress stimuli that would make more suitable candidates for therapeutic intervention.

Summary: At this juncture it is no longer unreasonable to suggest that further iterations of anti-Aβ therapies should be halted. Clinicians and researchers should instead direct their attention toward greater understanding of the biological function of Aβ both in healthy and demented brains, as well as the involvement of long-term chronic exposure to stress in the etiology of AD.

Figure 1

Comparison of the amyloid and adaptive response hypotheses.A. Amyloid Hypothesis Cognitive tests and amyloid imaging separate the total population into four distinct groups (1). These groups are: Normal Cognition (NC; 4), NC with Aβ accumulation (NC-Aβ; 2), Neurodegeneration-First AD (NDF-AD; 3), and Amyloid-First AD (AF-AD; 5). Under this hypothesis, only the AF-AD and NC groups (4,5) are going to be studied moving forward in EXPEDITION 3 as disease state and control, whereas the NC-Aβ and NDF-AD groups (2,3) are ignored, as they cannot be explained and do not fit the paradigm. B. Adaptive Response Hypothesis The total population (1) is differentiated by a set of stress variables (2) which may include, but are not limited to, oxidative stress, metabolism dysregulation (cholesterol homeostasis, insulin resistance, etc.), genetic factors, and inflammation response. These variables elicit an adaptive response in the brain and, depending on the nature and intensity of such response, the population falls into two groups, either Normal Cognition (NC) (3) or AD (4), both of which contain Aβ positive and negative subpopulations.