Why Amyloid Is Still a Target for Alzheimer Disease Clinical Trials

Abstract

See the response from https://doi.org/10.1111/jgs.15826.

Design, synthesis and biological evaluation of light-driven on–off multitarget AChE and MAO-B inhibitors

“…The inhibition of amyloid aggregation, supporting the so-called amyloid hypothesis in AD insurgence, is still a pursued target despite many failures of antiamyloid agents in clinical trials. 52 In our in vitro assay, the E / Z mixtures were tested at a concentration of 100 μM to reveal any putative activity to be further evaluated on pure E isomers. As listed in Table 1, no appreciable inhibition of Aβ 40 aggregation was found, except for 1a , whose 5,6-dimethoxyindane structure represents a known scaffold for efficient disruption of protein aggregation.…”

Discoveries and future significance of research into amyloid-beta/α7-containing nicotinic acetylcholine receptor (nAChR) interactions

“…Studies over approximately the last two decades have deemphasized or shown marginal contributions of neuritic plaques and neurofibrillary tangles to dementia [ 15 , 159 , 84 , 96 , 98 ]. In addition, repeated failures of plaque-removing therapies during clinical trials have brought the classical amyloid hypothesis into further doubt or, at the least, indicated that other factors may play more important roles earlier during disease development [ 106 , 60 , 89 , 88 ]. While a significant amount of evidence indicates that Aβ plays a causative and initiating role in the development of AD, only a limited number of anti-Aβ agents have proven effective in clinical trials.…”

Reply to: Why Amyloid Is Still a Target for Alzheimer's Disease

“…So far, hundreds of amyloid‐orientated clinical trials have disproved the hypothesis that brain amyloid causes AD . Professor Eric McDade elegantly proposes three scenarios of amyloid in Alzheimer dementia: harmless Aβ in scenario 1 and harmful Aβ in scenarios 2 and 3. McDade 2 then provides evidence for the toxic Aβ scenarios, although he acknowledges that Aβ is an important protein in the brain, possessing physiological functions; in terms of full length (40, 42, or 43 amino acids), conformational structure (monomer, oligomer, or fibril), and anatomical compartment (tissue or cerebrospinal fluid, cerebrocortical lobes or hippocampus, or parenchymal or vascular deposits), not all Aβ peptides are equal.…”