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

A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, A beta) oligomers as upstream pathogenic drivers of Alzheimer's disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of A beta provide compelling evidence that inhibition of A beta oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble A beta 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 epsilon 4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of A beta oligomers. These trials also show that inhibiting A beta 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 A beta oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of A beta oligomers at the clinical dose.