Abstract: Almost all patients >40 years of age with Down's syndrome (DS) develop the pathology characteristic of Alzheimer's disease: abundant β-amyloid plaques and neurofibrillary tangles. We have investigated the gene expression of β-amyloid protein precursor (APR) and τ in DS and age-matched control brains and found that levels of both mRNAs were significantly elevated in DS. Such up-regulation was not observed in two other neuronal proteins. A correlation between total APP and τ mRNA levels was also found in DS brain but distinct from the pattern observed in normal brain. Although a proportionality existed between APP-695 mRNA and three-repeat τ mRNA in DS, the proportionality between APP-751 mRNA and four-repeat τ mRNA, which is normally present, was not observed. Thus, DS brains are primarily characterized by the up-regulation of τ mRNA as well as APP mRNA and disruption of the coordinate expression between APP-751 and four-repeat τ.