The amyloid protein precursor (APP) of Alzheimer's disease (AD) is abundantly expressed in platelets, where its primary function remains undetermined. As an integral transmembrane protein, the release of APP from the membrane may be a critical event in AD. We examined the association of APP with human platelet membranes using a combination of alkali treatment and immunoprecipitation of the carboxyl-terminus of APP. Most of the platelet membrane-associated APP (APPMem) with molecular mass of 100 to 130 kD is removed with alkali treatment and is also truncated at the carboxyl-terminus. APPMem is present at least in part on the surface of the platelet. The full-length transmembrane form of APP, as a 140- to 150-kD minor species, is alkali resistant and is also present on the plasma membrane. In contrast, most of the APPMem from brain is full-length (possessing the carboxyl-terminus) with a molecular mass of 105 to 130 kD and is resistant to alkali treatment. Immunoelectron microscopy shows platelet APP to be localized to the alpha-granule. Activation of platelets results in a threefold increase in surface APP detectability. In plasma, the 130-kD APP-reactive band is increased in AD. We find that in the gray platelet syndrome, platelets contain reduced amounts of APP, with a corresponding reduction in plasma APP levels, suggesting that platelets are the major source of plasma APP. Our studies also identify an interaction of APP with platelet membranes which differs from that found in the brain, and raise the possibility of a receptor for APP in platelet membranes. Quantitative differences in the amounts of APPMem in platelets compared with brain also indicate regulation of the pathways that determine the cleavage of APP near its transmembrane domain. These pathways are a therapeutic target in AD, and may be easily amenable to investigation in platelets.