Stress as risk factor for Alzheimer's disease.

Prolonged stress predisposes susceptible individuals to a number of physiological disorders including cardiovascular disease, obesity and gastrointestinal disorders, as well as psychiatric and neurodegenerative disorders. Preclinical studies have suggested that manipulation of the glucocorticoid milieu can trigger cellular, molecular and behavioral derangement resembling the hallmarks of Alzheimer's Disease (AD). For example, stress or glucocorticoid administration can increase amyloid ß precursor protein and tau phosphorylation which are involved in synaptic dysfunction and neuronal death associated with AD. Although since AD was first described in 1906 at a conference in Tubingen, Germany by Alois Alzheimer our knowledge of neuropathological and neurochemical alterations of AD has been impressively increased, at present, pharmacotherapy is symptomatic at best and has no influence on the progression of the disorder. It is generally believed that most of the drugs developed as disease modifiers have failed in clinical trials because treatment started too late, i.e., after the clinical onset of AD. Because AD pathology begins several years prior to the clinical diagnosis, it is imperative to identify subjects at high risk to develop the disorder. Consequently, the search for putative risk factors has gained importance. ApoE4, diabetes/metabolic syndrome, cardiovascular disorders, and a low cognitive reserve are established risk factors for AD. The focus of this review is on stress and glucocorticoids as potential factors increasing the risk to develop AD.