| Abstract: | Evidence is fast accumulating which indicates that Alzheimer’s disease is a vascular disorder with neurodegenerative consequences rather than a neurodegenerative disorder with vascular consequences. It is proposed that two factors need to be present for AD to develop: (1) advanced ageing, (2) presence of a condition that lowers cerebral perfusion, such as a vascular-risk factor. The first factor introduces a normal but potentially insidious process that lowers cerebral blood flow in inverse relation to increased ageing; the second factor adds a crucial burden which further lowers brain perfusion and places vulnerable neurons in a state of high energy compromise leading to a cascade of neuronal metabolic turmoil. Convergence of the two factors above will culminate in a critically attained threshold of cerebral hypoperfusion (CATCH). CATCH is a hemodynamic microcirculatory insufficiency that will destabilize neurons, synapses, neurotransmission and cognitive function, creating in its wake a neurodegenerative state characterized by the formation of senile plaques, neurofibrillary tangles, amyloid angiopathy and in some cases, Lewy bodies. Since any of a considerable number of vascular-related conditions must be present in the ageing individual for cognition to be disturbed, CATCH identifies an important aspect of the heterogeneic disease profile assumed to be present in the AD syndrome. It is proposed that CATCH initiates AD by distorting regional brain capillary structure involving endothelial cell shape changes and impairment of nitric oxide (NO) release which affect signaling between the immune, cardiovascular and nervous systems. Evidence is presented that in many tissues there is a basal level of NO being produced and that the actions of several signaling molecules may initiate increases in basal NO levels. Moreover, these temporary increases in basal NO levels exert inhibitory cellular actions, via cellular conformational changes. Findings indicate that (a) constitutive NO is responsible for a basal or ‘tonal’ level of NO; (b) this NO keeps particular types of cells in a state of inhibition and (c) activation of these cells occurs through disinhibition. Consequently, tissues not maintaining a basal NO level are more prone to excitatory, immune, vascular and neural influences. Under such circumstances, these tissues cannot be down-regulated to normal basal levels, thus prolonging their excitatory state. Thus, the clinical convergence of advanced ageing in the presence of a chronic, pre-morbid vascular risk factor, can, in time, contribute to an endotheliopathy involving basal NO deficit, to the degree where regional metabolic dysfunction leads to cognitive meltdown and to progressive neurodegeneration characteristic of Alzheimer’s disease. |
