It is evident that, although an excessive production of APP may be the principal cause of βA4 generation in DS, other processes either singly or in combination must be considered to explain the neuropathological heterogeneity characteristic of AD. These include: 1. Syntheses of APP variants; 2. Altered secretase activity; 3. Modified activity of alternate pathway proteases; and 4. Altered ratios between kunitz-containing and kunitz-deficient isoforms (Fig. 4). Of particular significance is the recent finding of a calcium-activated serine protease that cleaves APP one amino acid upstream from βA4 (Abraham et al., 1991a). This enzyme may catalyze the first step of the alternative pathway when APP is altered posttranslationally or when the secretase activity is decreased in AD. Molecular biochemical technology has contributed substantially to recent advances in the understanding of this disease. However, further study of the pathological processes operative in Alzheimer's disease is required before effective therapy can be developed.