In recent years, some of the subcellular mechanisms that are deranged by the presence of intracellular or extracellular amyloid have been elucidated. The finding of a reduced number and enlargement of synapses in affected cortex early in the disease by DeKosky and Scheff and others could be interpreted as either the first sign of neuronal death or the result of the neuronal loss. Amyloid deposition would then be a later, secondary phenomenon. One hypothesis is that Alzheimer disease is a disorder of synaptic failure, as summarized by Querfurth and LaFerla. They summarize some of the subcellular derangements that may connect amyloid or tau deposition to neuronal cell loss; these include abnormal calcium regulation, inflammation, insulin signaling, cholesterol metabolism and aberrant cell-cycle reentry. These are complex and uncertain connections but they are among the most promising findings in this field of research.
It was long ago established that Alzheimer disease, contrary to views prevalent at that time, is not caused by any of the usual types of arteriosclerosis. On the other hand, several studies have indicated that the presence of cerebral infarctions, small or large, and of nondescript ischemic white matter disease accelerates the deposition of amyloid and the development of neurofibrillary tangles in the brains of Alzheimer patients (see further on); the mechanism of these interactions is not understood. Not surprisingly, cerebrovascular disease also exaggerates the rate of progression and degree of dementia. How this relates to the entity of arteriosclerotic, multiinfarct, or vascular dementia is not entirely clear. Without doubt, as discussed in Chap. 33, multiple cerebral strokes cause increasing deficits that cumulatively qualify as a dementia. At least some of the focal lesions that contribute to the cognitive syndrome can be identified clinically and there is a stepwise decline in function that corresponds to strokes. Admittedly, this type of vascular dementia may be more difficult to recognize when a number of the infarcts are of the relatively silent lacunar type or affect cerebral white matter diffusely; the mental capacities of such patients may then appear to fail in a gradual and continuous fashion, similarly to Alzheimer disease. Usually, a pseudobulbar state or deterioration in gait eventually accompanies the dementia of vascular disease. The subcortical white matter change of Binswanger disease causes similar diagnostic problems. We are inclined toward the view expressed in Chap. 20 and summarized in the commentary by Jagust that there is an undefined, and perhaps synergistic, interaction between strokes and progressive mental decline in patients with Alzheimer disease. Most often, in our experience, it is the degenerative condition of Alzheimer that explains the dementia. A similar relationship between Alzheimer disease and previous head injuries is tentative but has led to speculation that several types of brain injuries are conducive to the development of neurofibrillary tangles and amyloid deposition, as if they were part of a reparative response.