# APP (Amyloid precursor protein)

Amyloid precursor protein (APP) is a membrane-spanning protein. It is coded on chromosome 21 and found widely in your brain and nerves. How it is cut decides everything. There are two routes. In the harmless route ('non-amyloidogenic'), an enzyme (alpha-secretase) cuts APP right within the amyloid-beta sequence, so no amyloid forms. In the harmful route ('amyloidogenic'), two enzymes act in turn. First beta-secretase (called BACE1), then gamma-secretase. They release amyloid-beta fragments of 38 to 43 amino acids. The most clump-prone is Aβ42, central to plaque formation. Genetics drives the link home. Mutations in APP, and extra copies of the APP gene, cause inherited early-onset Alzheimer's. People with Down syndrome (trisomy 21) have a third APP copy. They develop Alzheimer's pathology almost universally by midlife. One protective variant, the Icelandic A673T, lowers BACE1 cutting and guards against Alzheimer's. That supports the amyloid hypothesis. The hypothesis gained new clinical weight with anti-amyloid antibodies. Those are lecanemab (FDA 2023, EU 2025) and donanemab (FDA 2024, EU 2025), for early symptomatic Alzheimer's.

## Sources

- Selkoe DJ, Hardy J. (2016). The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201606210
- O'Brien RJ, Wong PC. (2011). Amyloid Precursor Protein Processing and Alzheimer's Disease. Annual Review of Neuroscience. https://doi.org/10.1146/annurev-neuro-061010-113613

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_Canonical: https://longevity-austria.com/en/glossary/amyloid-precursor-protein · Part of Longevity Cities · Updated 2026-06-22_