Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression

Abstract

A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers of Alzheimer’s disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aβ provide compelling evidence that inhibition of Aβ oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble Aβ oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the ε4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of Aβ oligomers. These trials also show that inhibiting Aβ neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage Aβ oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of Aβ oligomers at the clinical dose.

Peptide backbone modifications of amyloid β (1–40) impact fibrillation behavior and neuronal toxicity

“…However, amyloid fibril formation does not follow only a single pathway, but occurs through several routes in the energy landscape 5 , 6 . Intermediates that are formed on the way include soluble oligomers, to which strong neurotoxicity is ascribed via different molecular mechanisms such as membrane disruption, receptor-binding followed by activation of signaling pathways or glutamatergic neuronal hyperactivation 7 – 9 .…”

New therapeutic opportunities for Alzheimer disease

“…Regarding safety, ARIA-E and Amyloid-related imaging abnormalities-haemosiderin (ARIA-H) appear due to damage to the blood-brain barrier in the process of immune-mediated clearance of amyloid accumulated in the brain with anti-amyloid therapy [27]. Aducanumab and gantenerumab occurred in approximately 30%, with ARIA-E occurring more frequently in the high-dose aducanumab group and lecanemab, which has a relatively low affinity for amyloid plaque, occurred in about 10% [27]. ARIA usually appears at the beginning of treatment and is mostly asymptomatic.…”

Artificial Intelligence for Alzheimer’s Disease: Promise or Challenge?

“…Despite ample research effort, we still do not have a cure capable of modifying and/or halting the course of the disease. Some clinical trials are ongoing, especially with the use of monoclonal antibodies targeting Aβ peptides, modified Aβ species, and monomeric as well as aggregated oligomers, which have shown to be safe and have clinical efficacy in AD patients [23]. However, AI pipelines can be applied in automatic compound synthesis in order to analyze the literature and high-throughput compound screening data, to perform an initial molecular screening and automated chemical synthesis [24].…”