A Unifying Hypothesis of Alzheimer's Disease. II. Pathophysiological Processes

The age-related loss of hormonal balance puts the homeostatic calcium±energy±antioxidant triangle under stress. The energetic compromise enhances b-amyloid protein formation and tau protein hyperphosphorylation, both cellular stress responses, which may give rise to di€use plaque and neuro®brillary tangle formation during normal ageing. Facilitated by a multitude of risk factors (discussed in part III of this series), the age-related processes lead into the pathophysiological events of Alzheimer's disease (AD). In AD, the hormonal imbalance is further aggravated with progressively detrimental sequelae for the calcium±energy±redox homeostasis and for both amyloid protein precursor and tau protein metabolism. The immune system as an integral component of the neuroendocrine immunological network is subject to the deteriorating endocrinological balance and displays a cellular and humoral acute phase-type reaction. In an orchestrated action, an in ̄ammatory response is mounted in which activated microand astro-glia and their secreted in ̄ammatory mediators and matrix constituents elicit the transformation of di€use into neuritic plaques which, secondarily, may induce further tissue damage. Importantly, the AD brain is characterized by the microglial inability to clear the brain of the deposited material. The pathophysiological processes lead to functional and structural impairments of neuronal plasticity, a compromise of the neuronal network and, eventually, to cell death. Conspicuously, these alterations do not uniformly a€ect all brain regions but manifest with a temporal and topographical speci®city vulnerable areas and nerve cell populations. Copyright # 1999 John Wiley & Sons, Ltd.