Abstract :
Much of the controversy about the “amyloid cascade hypothesis” may reflect unrecognized differences in the use of language, including the use of the word “cause.” This commentary proposes that the term Alzheimer disease refer to the neuropathological entity and the term Alzheimer dementia to clinical dementia in people who also have Alzheimer neuropathology. The ultimate causes of Alzheimer disease are proposed to be aging, environmental stresses, and genetic predispositions. The fundamental cause of Alzheimer dementia is proposed to be Alzheimer disease, i.e. the neurobiological abnormalities in Alzheimer brain. The neurobiology of Alzheimer disease includes changes that may initially be adaptive but can become excessive and thereby harmful; they include increased expression of APP with accumulation of potentially damaging peptides such as Aβ, inflammation, and increased ROS activity. The neurobiological abnormality that is the proximate cause of Alzheimer dementia appears to be decreases in cerebral metabolic rate. Decreased metabolism occurs not only in this but in essentially all dementias, and impairing brain metabolism induces neuropsychological deficits characteristic of dementias. The immediate cause of Alzheimer dementia is proposed to be deficiencies in signaling, both intracellular and intercellular (neurotransmission), that follow directly from the decrease in cerebrometabolic rate.
