Amyloid-beta soluble oligomer (AβO) (AβO)

Amyloid-beta soluble oligomers (AβOs) are small, non-fibrillar aggregates of the amyloid-beta peptide that are widely considered the most neurotoxic species in Alzheimer's disease (Sengupta et al., 2016, PMID: 27010080). Unlike insoluble amyloid plaques, these soluble assemblies can diffuse through the brain parenchyma and interact with various synaptic receptors, leading to the disruption of long-term potentiation and subsequent synaptic loss (Cline et al., 2018, PMID: 29914151). AβOs are known to trigger a cascade of pathological events, including neuroinflammation, oxidative stress, and the hyperphosphorylation of tau protein (Haass & Selkoe, 2007, PMID: 17261848). Therapeutic interventions, such as the monoclonal antibody lecanemab, are designed to selectively bind these soluble aggregates and protofibrils to promote their clearance and neutralize their toxicity (Eisai, 2023). Clinical trials have demonstrated that reducing the burden of these soluble species can significantly slow the progression of cognitive decline in early-stage Alzheimer's patients (van Dyck et al., 2023, NEJM). However, targeting these species is associated with specific safety risks, most notably Amyloid-Related Imaging Abnormalities (ARIA), which require careful monitoring via MRI (FDA Leqembi Label, 2023). The focus on AβOs represents a shift in the amyloid hypothesis from total plaque removal to the targeting of specific toxic intermediate species.

Other names

Aβ oligomerAmyloid-beta-derived diffusible ligand (ADDL)Soluble Aβ aggregateAmyloid-beta protofibrilSoluble amyloid-beta assembly

Selective binding to soluble amyloid-beta oligomers and protofibrils to neutralize their neurotoxic effects and facilitate their clearance from the brain via microglial phagocytosis (Acumen Pharmaceuticals, 2024; Eisai, 2023).