A four- to fivefold overexpression of the gene for the Alzheimer amyloid precursor protein (APP) in individuals with Down's syndrome (DS) appears to be responsible for the fifty year earlier onset of Alzheimer's disease pathology in DS compared to the normal population. Elucidation of the mechanisms regulating the expression of the human APP gene might therefore be an important step forward in understanding the processes leading to Alzheimer's disease. Recently, an activating DNA fragment proximal to the transcriptional start site of the APP gene was identified, composed of two GC-elements, A and C, both required for full transcriptional activation (1). Here I present evidence that the transcription factor Sp1 can bind to element A and that another specific complex, called C2A, can be observed, which covers a region overlapping with the Sp1 binding site on the APP promoter. Gene transfer experiments with a truncated version of the APP promoter containing mutated binding sites for the factors mentioned above support that at least two different and independent regulatory pathways for APP gene expression might exist. An imbalance between these pathways is proposed to be a putative risk factor for the development of Alzheimer's disease.