APP (Amyloid precursor protein)

Amyloid precursor protein is a type I transmembrane glycoprotein encoded on chromosome 21 and expressed widely in the central nervous system. In the non-amyloidogenic pathway alpha-secretase cleaves APP within the amyloid-beta sequence; in the amyloidogenic pathway beta-secretase (BACE1) then gamma-secretase release amyloid-beta peptides of 38 to 43 residues, of which Abeta42 is the most aggregation-prone and central to plaque formation. Pathogenic missense mutations in APP and duplications of the APP locus cause autosomal-dominant early-onset Alzheimer disease; trisomy 21 (Down syndrome) produces a third APP copy and near-universal Alzheimer pathology by midlife. The Icelandic A673T variant lowers BACE1 cleavage and protects against Alzheimer disease, providing genetic support for the amyloid hypothesis. The amyloid hypothesis gained renewed clinical relevance with the approval of anti-amyloid monoclonal antibodies — lecanemab (FDA 2023, EU 2025) and donanemab (FDA 2024, EU 2025) — for early symptomatic Alzheimer disease.