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

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.

Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier

“…This study, as well as other human and animal studies, helps to explain the marginal responses or actual failure of recent intravenous Aβ antibody (e.g., Solanezumab, Bapineuzumab, Crenezumab) infusion clinical trials. These trials appear to depend upon the Aβ antibodies enhancing efflux transport of Aβ across the BBB (Prins and Scheltens, 2013; Castello, et al 2014; Toyn, 2015; Godyn, et al 2016; Bouter, et al 2015; Fuller et al 2015). Alternatively the poor performance of Aβ antibody therapy may be the multi-morbidity of a number of pathologies seen in the brains of the AD and non-demented elderly, e.g., Lewy body disease, various tauopathies and cerebrovascular disease (Dugger et al, 2014; Attems et al 2013; Echavarri et al 2012).…”

Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease

“…Lately, trials with antibody treatment and immunizations against Aβ have tried to prevent plaque formation, although without overwhelmingly positive results [40]. A target in preventing Aβ plaque formation is the prevention of production of Aβ peptides that are prone to aggregate.…”

The amyloid hypothesis is too good to be true

“…What I say in this paper has been said in other words by many others [24,25,60,[124][125][126][127][128][129]. I cite one more, a great paper by Banik et al [130] who "critically reviewed past literature (1990-2014)" and argued Alzheimer research and clinical trials have been "hindered by the domination of the amyloid hypothesis", and went on to write: "A greater variety of potential disease mechanisms must be entertained to enhance progress."…”