The human beta-amyloid protein precursor (beta-APP) gene (symbol APP) shows variable levels of expression in different human tissues, including brain. Because at least a moderate level of beta-APP expression is probably a necessary, although not sufficient, condition for diseases associated with pathologic deposition of beta-APP proteolytic products (such as the A beta peptide), we sought to identify factors in the 5' promoter of the human APP gene that may regulate tissue-specific expression of the APP gene. We report that sequences upstream from -500 bp in the APP promoter display complex, tissue-specific patterns of methylation. Furthermore, different patterns of methylation were observed even in DNA from different regions of brain. These differentially methylated sequences are able to bind nuclear proteins expressed in brain and HeLa cells and are also methylated in neocortex of nonhuman primates. Because these methylation patterns crudely reflect differences in APP expression, they may represent one mechanism for the tissue-specific regulation of APP expression.