Amyloid-beta (Aβ) protofibrils and fibrils (Aβ aggregates)

Aggregated amyloid-beta (Aβ) protofibrils and fibrils are pathological assemblies of the Aβ peptide, primarily Aβ42, which play a central role in the amyloid cascade hypothesis of Alzheimer's disease (Hardy & Higgins, 1992, Science). These aggregates form through the misfolding and polymerization of monomeric Aβ into soluble protofibrils and eventually into insoluble fibrils that constitute extracellular senile plaques (Soto & Pritzkow, 2018, Nature Neuroscience). Protofibrils, in particular, are considered highly neurotoxic species that disrupt synaptic function and induce neuroinflammation (Walsh et al., 2002, Nature). Therapeutic strategies targeting these aggregates involve monoclonal antibodies designed to recognize specific conformational epitopes, facilitating the clearance of existing deposits via microglial phagocytosis (van Dyck et al., 2023, NEJM). Recent clinical successes with drugs like lecanemab and donanemab have validated these aggregated forms as viable therapeutic targets for slowing cognitive decline in early-stage patients (Sims et al., 2023, JAMA). These drugs differ in their affinity for various aggregated species, with some specifically targeting soluble protofibrils and others targeting insoluble plaque-associated fibrils (Eisai, 2023; Eli Lilly, 2024). However, treatment is often associated with safety concerns such as amyloid-related imaging abnormalities (ARIA), which include brain edema and microhemorrhages (Sperling et al., 2011, Alzheimer's & Dementia). Monitoring these targets through PET imaging and fluid biomarkers is essential for assessing treatment efficacy and patient safety (Johnson et al., 2013, Radiology).

Other names

Amyloid-beta aggregatesAβ protofibrilsAβ fibrilsAmyloid-beta plaquesMisfolded amyloid-betaAβ42 aggregates

Monoclonal antibodies bind to specific conformational epitopes on aggregated amyloid-beta species, such as protofibrils or fibrils, to facilitate their clearance via microglia-mediated phagocytosis and prevent further deposition into insoluble plaques (van Dyck et al., 2023, NEJM; Sims et al., 2023, JAMA).