Soluble pool of A beta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease

Genetic evidence strongly supports the view that A beta amyloid production is central to the cause of Alzheimer's disease. The kinetics, compartmentat ion, and form of A beta and its temporal relation to the neurodegenerative process remain uncertain. The levels of soluble and insoluble A beta were d etermined by using western blot techniques, and the findings were assessed in relation to indices of severity of disease. The mean level of soluble A beta is increased threefold in Alzheimer's disease and correlates highly wi th markers of disease severity. In contrast, the level of insoluble A beta (also a measure of total amyloid load) is found only to discriminate Alzhei mer's disease from controls, and does not correlate with disease severity o r numbers of amyloid plaques. These findings support the concept of several interacting pools of A beta, that is, a large relatively static insoluble pool that is derived from a constantly turning over smaller soluble pool. T he latter may exist in both intracellular and extracellular compartments, a nd contain the basic forms of A beta that cause neurodegeneration. Reducing the levels of these soluble A beta species by threefold to levels found in normal controls might prove to be a goal of future therapeutic interventio n.