APP and Alzheimer disease: Rare APP promoter mutations that significantly increase APP expression levels are associated with early-onset AD.1 Mild (∼20%) APP overexpression is sufficient to increase AD risk in the general population.2 Genomic duplication of the APP locus leads to autosomal dominant early-onset AD.3 Similarly, individuals with Down syndrome (trisomy of chromosome 21) harbour three copies of the APP gene and typically develop progressive AD with characteristic neuropathological features including amyloid plaques, neurofibrillary tangles and neuronal loss.