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

Abstract

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 accordance with the concept that AD is a metabolic disease, these risk factors deteriorate the homeostasis of the Ca(2+)-energy-redox triangle and disrupt the cerebral reserve capacity under metabolic stress. The major genetic risk factors (APP and presenilin mutations, Down's syndrome, apolipoprotein E4) are associated with a compromise of the homeostatic triangle. The pathophysiological processes leading to this vulnerability remain elusive at present, while mitochondrial mutations can be plausibly integrated into the metabolic scenario. The metabolic leitmotif is particularly evident with medical risk factors which are associated with an impaired cerebral perfusion, such as cerebrovascular diseases including stroke, cardiovascular diseases, hypo- and hypertension. Traumatic brain injury represents another example due to the persistent metabolic stress following the acute event. Thyroid diseases have detrimental sequela for cerebral metabolism as well. Furthermore, major depression and presumably chronic stress endanger susceptible brain areas mediated by a host of hormonal imbalances, particularly the HPA-axis dysregulation. Sociocultural and lifestyle factors like education, physical activity, diet and smoking may also modulate the individual risk affecting both reserve capacity and vulnerability. The pathophysiological relevance of trace metals, including aluminum and iron, is highly controversial; at any rate, they may adversely affect cellular defences, antioxidant competence in particular. The relative contribution of these factors, however, is as individual as the pattern of the factors. In familial AD, the genetic factors clearly drive the sequence of events. A strong interaction of fat metabolism and apoE polymorphism is suggested by intercultural epidemiological findings. In cultures, less plagued by the 'blessings' of the 'cafeteria diet-sedentary' Western lifestyle, apoE4 appears to be not a risk factor for AD. This 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 interaction. Copyright 2000 John Wiley & Sons, Ltd.

Will a Healthy Lifestyle Help Prevent Alzheimer's Disease?

“…Identifying genetic factors may provide valuable information for targeting prevention and treatment strategies to individuals at increased risk for AD (30).…”

“…Head injuries may reduce brain reserve or induce alterations in neuronal metabolism or circuitry (30). One study suggests that head trauma is only a risk factor for individuals who carry the ApoE ε4 allele, although the mechanism for this interaction is unclear (52).…”

“…Both diseases cause decreased cerebral perfusion (oxygenation), which leads to lowered brain metabolism, brain lesions, and initiation of chronic pathophysiologic processes, all of which are implicated in AD (30). Cerebral infarcts, which result from strokes, are frequently detected in AD brains, and patients who have suffered a stroke experience reduced cognitive function, more rapid cognitive decline, and are more prone to develop AD (80).…”

A Pilot Study of Gene/Gene and Gene/Environment Interactions in Alzheimer Disease

“…9 As with most complex diseases, LOAD is likely to be influenced not only by genetic, but also by environmental components. 10,11 Based on outcomes of studies in twins, Plassman et al 12 reported simple heritability estimates among various European populations at approximately 0.8, suggesting that environmental factors account for approximately 20% of variance in population susceptibility to AD.…”

Assessment of Physico-Chemical Characters and Heavy Metal Distribution Along the Panchganga River, Ms, India

“…[15] Increased zinc intake can cause demyelinating diseases in human beings [16] and aluminium is responsible for development of dementia-type syndromes and postulated as one of the etiological agents of Alzheimer's disease. [17,18,19,20] Though iron is a bioessential element, its excess accumulation causes nephrotoxicity, induction of renal cell and heptacellular carcinoma have been well documented in the literature. [21,22,23,24] www.wjpps.com …”