Because amyloid precursor protein (APP) fragments exist in many tissues throughout the body, including the fluid compartments of blood, they have been the focus of numerous investigations into their potential as a biomarker of Alzheimer's disease. Using immunohistochemistry, immunoelectron microscopy, Western blot, and quantitative real-time-polymerase chain reaction (qRT-PCR) analysis we examined whether APP processing in leukocytes is analogous to APP processing in the brain. We show APP immunoreactivity at light and electron microscopic levels in the cytoplasm and nucleus of peripheral blood leukocytes (PBL) yet our Western blot analysis data demonstrated that brain and PBL contain different APP fragments and differentially expressed APP processing enzymes. A Disintegrin and Metalloproteinase domain 10 (ADAM10), nicastrin, and beta-secretase 2 (BACE2) were present in brain but were undetected in PBL. Presenilin 1 and beta-secretase 1 (BACE1) were detected in both tissues but showed different patterns in Western blots. Quantitative PCR results identified Neprilysin as the only processing enzyme we interrogated in which Western and quantitative PCR data coincided. Although our data on differential processing of APP in brain and PBL point to exercising caution when generalizing between blood and brain with regard to mechanisms, they have no implications regarding utility as biomarkers.