Aberrant expression of the amyloid precursor protein (APP) gene may contribute to the beta-amyloid deposition seen in Alzheimer's disease and Down syndrome patients. Genomic DNA was isolated from human brain tissue and digested with HpaII, an enzyme sensitive to CpG methylation. Southern-blot analysis revealed the absence of methylation at a site in the APP gene of an Alzheimer's disease subject. This site was methylated in a nondemented subject and a subject with a non-Alzheimer's type of dementia (Pick's disease). This is the first report of an epigenetic defect in an Alzheimer's disease patient and the observation suggests that hypomethylation of the APP gene may be one of several factors contributing to aberrant gene expression in Alzheimer's disease.