Cerebral β/A4-amyloid deposition is a key feature of the neuropathology of Alzheimer's disease. β/A4-amyloid is the principal component of parenchymal and cerebrovascular amyloid deposits and is derived from a transmembrane precursor, the β/A4-amyloid precursor protein (APP). In its metabolism, the APP molecule can enter a protein processing pathway which leads to cleavage within the β/A4-amyloid domain and thus prevents β/A4-amyloid production. Stimulation of certain protein phosphorylation signal transduction pathways leads to increased processing of APP by this nonamyloidogenic pathway at the expense of other potentially amyloidogenic pathways. Mutagenesis of target phosphorylation sites in APP fails to modify the stimulatory effect on APP processing, suggesting that APP processing enzymes and/or trafficking proteins (rather than APP itself) are the important mediator(s) which specify this regulation. Some of our current efforts are focussed on distinguishing among several possible candidate mediators in order to determine which of these is most important in diminishing amyloid production. By modulating the relative activities of nonamyloidogenic versus amyloidogenic pathways for APP degradation in brain, cerebral amyloid deposition might be prevented.