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

John David Jeppson,Michael A Castello,Salvador Soriano

doi:10.1186/s12883-014-0169-0

Abstract

BackgroundHigh-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.DiscussionThese 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.SummaryAt 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.

Highlights

High-profile Phase 3 clinical trials of bapineuzumab and solanezumab, antibodies targeted at amyloid-beta (Aβ) removal, have failed to meet their primary endpoints
Clinicians and researchers should instead direct their attention toward greater understanding of the biological function of Amyloid beta (Aβ) both in healthy and demented brains, as well as the involvement of long-term chronic exposure to stress in the etiology of Alzheimer’s disease (AD)
Along with a chorus of others, we have previously argued against the assumption that Aβ accumulation is the primary early pathogenic trigger of AD [4,5,6,7,8]

Summary

Discussion

We submit that such course of action is logically flawed on two different fronts. Firstly, current imaging methods cannot detect the soluble Aβ oligomers that solanezumab is thought to remove but that are, according to the amyloid hypothesis itself, the bona fide pathogenic trigger of the disease [12,13,14]. These stress stimuli constitute the bona fide pathogenic triggers of late onset AD and, would be suitable candidates for therapeutic intervention [5,6,7,32,36] In this model, illustrated, the total population (Figure 1B, 1) can be affected by chronic stress stimuli (Figure 1B, 2) which may include, but are not limited to, oxidative stress, metabolic dysregulation (cholesterol homeostasis, insulin resistance, etc.), genetic factors, and inflammatory response [7,36]. This leads to the observed division, shown, into individuals with normal cognition (NC; Figure 1B, 3) and those clinically diagnosed with AD (AD; Figure 1B, 4), both of which may be further divided into Aβ positive and Aβ negative subpopulations [6,32] According to this view, therapeutic approaches must address the biology of the chronic stressors that initiate the disease, not the Aβ accumulation that (unlike in FAD) may, or may not, occur during the course of the disease. Clinicians and researchers should instead direct their attention toward better understanding of the biological function of Aβ in the healthy brain, and the ways in which chronic stress over decades can negatively affect the brain

Background

Summary

Findings

24. Bloom GS

35. Marchesi VT