The processing of the Amyloid Precursor Protein (APP) is a critical event in the formation of amyloid plaques which are composed of the 4kDa amyloid beta-peptide (Abeta). Processing of APP occurs through a non-amyloidogenic pathway, mediated by initial alpha-secretase cleavage or through an amyloidogenic pathway via sequential cleavage by beta- and gamma-secretase enzymes, which produces Abeta peptides. Currently, the diagnosis of probable or possible Alzheimer's disease (AD) is primarily based on neuropsychological and neuroradiological assessment. Recent reports indicate that platelet beta-secretase activity is moderately increased in patients with AD and mild cognitive impairment (MCI). To our knowledge platelet alpha-secretase activity has not yet been explored in this context and estimation of the ratio of the activities of alpha- and beta-secretase in platelets may represent a useful surrogate marker of the balance between the two pathways of APP metabolism and be of importance for the diagnosis of AD. We therefore considered it of interest to develop assays of platelet alpha- and beta-secretase activities suitable for such clinical investigations. Application of these assays to a Swedish population failed to uncover an effect of AD or MCI on individual platelet secretase activities or the secretase ratio. However, we did observe an inverse correlation between plasma triacylglycerol levels and the secretase ratio. The results are discussed in the context of the clinical usefulness of the secretase ratio as a biochemical adjunct to the diagnosis of AD.