Abeta

Abeta, or amyloid beta, is a family of peptide fragments derived from the amyloid precursor protein (APP). Abeta is produced when APP is sequentially cleaved by beta-secretase and gamma-secretase. The predominant brain isoforms are Abeta40 and Abeta42, with Abeta42 more prone to aggregation.

Under normal conditions, Abeta is produced and cleared at low levels. Aging or genetic factors can disturb this balance, allowing Abeta to accumulate and assemble into soluble oligomers, insoluble fibrils, and plaques, which are characteristic of Alzheimer's disease pathology.

Soluble Abeta oligomers are believed to contribute to synaptic dysfunction and neuroinflammation, whereas plaques are a histopathological hallmark that correlates imperfectly with disease severity.

Genetic factors influence Abeta biology. Rare familial mutations in APP, PSEN1, and PSEN2 can increase Abeta42 production or aggregation. In Down syndrome, APP gene dosage elevates Abeta production. Most sporadic cases involve multiple risk factors and APOE genotype.

Detection uses biomarkers such as reduced cerebrospinal fluid Abeta42 and a decreased Abeta42/Abeta40 ratio, and amyloid PET imaging that visualizes brain plaques.

Therapeutic approaches target Abeta production or clearance. Beta- or gamma-secretase inhibitors aim to reduce generation, while monoclonal antibodies target Abeta species for clearance. Clinical results have been mixed, highlighting ongoing debates about the causal role of Abeta and patient selection.