Eric Siemers, MD, Acumen Pharmaceuticals, Charlottesville, VA, discusses the decades-long journey to understanding Alzheimer’s disease. Contrary to the longstanding amyloid hypothesis, recent findings indicate that the soluble oligomers of amyloid-β (Aβ) are the toxic molecules, not the Aβ monomers or fibrils which constitute plaques. Experiments reveal that these globular oligomers disrupt long term potentiation, induce intracellular calcium influx, and lead to the hyperphosphorylation of tau. The oligomer hypothesis identifies these soluble oligomers as the key drivers of Alzheimer’s pathology, positioning them as the best therapeutic targets. ACU193, is an investigation monoclonal antibody that specifically targets these oligomers. While the FDA-approved antibody lecanemab targets protofibrils, which differ in shape from oligomers but shares solubility and toxicity, ACU193 stands out as the sole antibody capable of accurately testing the oligomer hypothesis. This interview took place at the Clinical Trials on Alzheimer’s Disease (CTAD) congress 2023 in Boston, MA.
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