ABSTRACT Potentially toxic amyloid β‐peptide (Aβ) in Alzheimer's disease (AD) is generated from a family of Aβ‐containing precursor proteins (APP), which is regulated via the 5′‐untranslated region (5′‐ UTR) of its mRNA. We analyzed 5′‐UTRs of the APP superfamily, including amyloid plaque‐ forming and non‐amyloid plaque‐forming species, and of prions (27 different DNA sequences). A “CAGA” sequence proximal to the “ATG” start codon was present in a location unique to APP genes of amyloid plaque‐forming species and absent in all other genes surveyed. This CAGA box is immediately upstream of an interleukin‐1‐responsive element (acute box). In addition, the proximal CAGA box is predicted to appear on a stem‐loop structure in both human and guinea pig APP mRNA. This stem‐loop is part of a predicted bulge‐loop that encompasses a known iron regulatory element (IRE). Electrophoretic mobility shift with segments of the APP 5′‐UTR showed that a region with the proximal CAGA sequence binds nuclear proteins, and this UTR fragment is active in a reporter gene functional assay. Thus, the 5′‐UTR in the human APP but not those of APP‐like proteins contains a specific region that may participate in APP regulation and may determine a more general model for amyloid generation as seen in AD. The 5′‐UTR of human APP contains several interesting control elements, such as an acute box element, a CAGA box, an IRE, and a transforming growth factor‐β‐responsive element, that could control APP expression and provide suitable and specific drug targets for AD.