In a series of ยฎve papers, evidence from neurobiology, endocrinology and immunology is integrated into a holistic, coherent hypothesis accommodating genetic, medical and environmental risk factors into a cascade of pathophysiological events that leads to the clinical manifestation of Alzheimer's disease (AD). The perturbation of the calcium-energy-oxidative stress triangle emerges as pathophysiological leitmotif of ageing and AD. Cellular Ca 2 homeostasis and energy metabolism are closely interdependent. Ca 2 ions regulate the activity of a variety of ratelimiting enzymes of the tricarboxylic acid cycle and respiratory chain. Under physiological circumstances, the supply of energy according to demand is regulated by Ca 2 cycling across mitochondrial membranes. In certain pathological conditions, Ca 2 uncouples electron transfer and oxidative phosphorylation and increases the mitochondrial production of oxygen radicals which in tandem with Ca 2 precipitate the breakdown of mitochondrial function and structure. As most important risk factor, ageing sets the stage for the development of AD. The delicate regulation of the neuroendocrine network which physiologically modulates the Ca 2 -energy-redox homeostasis, deteriorates in ageing, compromising the hormonal balance between neurotrophic/protective and neuroaggressive factors. Thus, levels and/or signal transduction pathways of neurotrophic-factors such as neuropeptide Y, neurotrophins, DHEA/ DHEAS, gonadal hormones, melatonin, insulin, insulin-like growth factors, somatostatin, thyroid hormones, and substance P decay, paralleled by the compromise of the hypothalmic-pituitary-adrenal (HPA)-axis feedback inhibition leading to a hyperresponsiveness to stress and a loss of diurnal rhythm of secretion of neuroaggressive glucocorticoids. Both add up to disrupt Ca 2 and energy homeostasis, put the nerve cells under metabolic and oxidative stress and lead to a compromise of neuronal excitability, signal transduction processes and neuronal plasticity. Subject to the same endocrinological dysregulation, the ageing immune system exhibits a primitive response pattern with impairment of speciยฎc cellular and activation of unspeciยฎc humoral and microglial immune responses. Thus, the ageing-related concerted perturbation of the homeostatic control in the neuroendocrinoimmunological network creates phenomena which in many aspects are qualitatively similar to changes in AD and lay the foundations for the development of the disease.