A unifying hypothesis of Alzheimer's disease. III. Risk factors

Normal ageing and Alzheimer's disease (AD) have many features in common and , in many respects, both conditions only differ by quantitative criteria. A variety of genetic, medical and environmental factors modulate the ageing- related processes leading: the brain into the devastation of AD. In accorda nce with the concept that AD is a metabolic disease, these risk factors det eriorate the homeostasis of the Ca2+-energy-redox triangle and disrupt the cerebral reserve capacity under metabolic stress. The major genetic risk fa ctors (APP and presenilin mutations, Down's syndrome, apolipoprotein E4) ar e associated with a compromise of the homeostatic triangle. The pathophysio logical processes leading to this vulnerability remain elusive at present, while mitochondrial mutations can be plausibly integrated into the metaboli c scenario. The metabolic leitmotif particularly evident with medical risk factors which are associated with an impaired cerebral perfusion, such as c erebrovascular diseases including stroke, cardiovascular diseases, hypo- an d hypertension. Traumatic brain injury represents another example due to th e persistent metabolic stress following the acute event. Thyroid diseases h ave detrimental sequela for cerebral metabolism as well. Further more, majo r depression and presumably chronic stress endanger susceptible brain areas mediated by a host of hormonal imbalances, particularly the HPA-axis dysre gulation. Sociocultural and lifestyle factors like education, physical acti vity, diet and smoking may also modulate the individual risk affecting both reserve capacity and vulnerability. The pathophysiological relevance of tr ace metals, including aluminum and iron, is highly controversial; at any ra te, they may adversely affect cellular defences, antioxidant competence in particular. The relative contribution of these factors, however, is as indi vidual as the pattern of the factors. In familial AD, the genetic factors c learly drive the sequence of events. A strong interaction of fat metabolism and apoE polymorphism is suggested by intercultural epidemiological findin gs. In cultures, less plagued by the 'blessings' of the 'cafeteria diet-sed entary' Western lifestyle, apoE4 appears to be not a risk factor for AD. Th is intriguing evidence suggests that, analogous to cardiovascular diseases. apoE4 requires a hyperlipidaemic lifestyle to manifest as AD risk factor. Overall, the etiology of AD is a key paradigm for a gene-environment intera ction. Copyright (C) 2000 John Wiley & Sons, Ltd.