Fibrillar beta-amyloid (Aβ fibril)

Fibrillar beta-amyloid aggregates are insoluble, highly ordered protein structures that serve as a primary pathological hallmark of Alzheimer's disease. These aggregates are formed from the amyloid-beta (Aβ) peptide, a product of the sequential cleavage of amyloid precursor protein (APP) by beta-secretase and gamma-secretase (Hardy & Higgins, Science 1992). In the disease state, Aβ monomers misfold and polymerize into oligomers and eventually into the stable, cross-beta sheet fibrils that constitute extracellular senile plaques. These fibrillar deposits are thought to contribute to neurodegeneration by inducing neuroinflammation, disrupting synaptic plasticity, and promoting the spread of tau pathology. As a therapeutic target, fibrillar Aβ is the focus of several monoclonal antibodies, such as lecanemab and donanemab, which are designed to bind specifically to the aggregated forms of the protein. These therapies aim to reduce the overall plaque burden in the brain by stimulating microglial-mediated clearance, which has been shown to correlate with a slowing of cognitive decline in clinical trials (van Dyck et al., NEJM 2023). However, targeting these aggregates is associated with significant safety risks, most notably amyloid-related imaging abnormalities (ARIA), which require careful monitoring during treatment (Sperling et al., Alzheimer's & Dementia 2011).

Other names

Amyloid-beta plaqueAmyloid-beta aggregateSenile plaqueFibrillar Aβ42Aβ aggregate

Monoclonal antibodies bind to the insoluble fibrillar form of amyloid-beta to induce Fc-receptor mediated phagocytosis by microglia, leading to the clearance of existing plaques from the brain parenchyma (van Dyck et al., NEJM 2023; Sims et al., JAMA 2023).