IMPAIRED BRAIN MICROCIRCULATION MAY TRIGGER ALZHEIMERS-DISEASE

A working hypothesis on the pathogenesis of Alzheimer's disease (AD) is presented. The model is based on recent ultrastructural and classic histologic findings showing extensive and characteristic distortion of brain capillaries in Alzheimer brains. Brain capillary distortion induces normal laminar flow to become microturbulent or ''disturbed,'' an outcome which over the course of many years can modify hemorheologic and hemodynamic flow patterns. As flow patterns become disturbed, micronutrient delivery to the brain is reduced thus compromising neurono-glial interaction. Catabolic outflow of CNS waste products is also depressed. When ischemic sensitive neurons, particularly in the CAI sector, are unable to meet energy demands from lowered energy supply, they release astroglial mitogens signalling reactive astrocytes to proliferate. The resulting neuronal energy crisis is consequently complicated by the increased density of reactive astrocytes which ostensibly contribute to senile plaque development and neurofibrillary tangle formation as competition for nerve tissue space increases. The suboptimal delivery of glucose, oxygen, essential nutrients and protease regulators in AD brain becomes progressively unpredictable and in time yields to a linear decline of neurochemical, morphologic and cognitive functions.