Selective Cerebrocortical Regional, Laminar, Modular and Cellular Vulnerability and Sparing in Alzheimer’s Disease: Unexploited Clues to Pathogenesis, Pathophysiology, Molecular- and Systems-Level Hypothesis Generation and Experimental Testing

Abstract

Virtually all current hypotheses on the pathogenesis and pathophysiology of Alzheimer’s disease rely on an unvoiced “amorphous” concept of the brain that essentially ignores its highly complex organization at the systems neuroscience level. This is especially true for the cerebral cortex, which happens to be the main target of the disorder and arguably the most complex structure of the entire brain. Here I review increasing evidence that the involvement of the cortex – while abundant – is not diffuse, random, or chaotic. In fact, the highly stereotyped patterns of the three-dimensional involvement of the cerebral cortex indicate that the pathobiological process targets highly selected cells and both anatomically and functionally unique multicellular arrays, while closely situated elements appear considerably resistant to the disease process. This remarkable dichotomy seems to apply pancortically and has essentially escaped recognition by most students of the disorder. Not surprisingly, there is no explanation for the selective involvement versus sparing of circuitry that is immediately adjacent of one another, and this notion seems conspicuously absent from virtually all models of the disorder. In fact, none have so far ever addressed the now highly probable central role of the modular organization of this region in the emerging pattern of vulnerability versus resistance to the disease process. This situation calls for an integration of at least the molecular and the systems neuroscience approaches to formulate new hypotheses on the pathogenesis and pathophysiology of Alzheimer’s disease, in order to enter a new stage in the elucidation of the disorder that accounts better for the factors that make certain neuronal assemblies more vulnerable – while others seem to be distinctly resistant – and precisely how this helps accounts for the clinical manifestations of the disease. Recent observations in animal models of some of the factors that may influence the selectivity of the disease process in the cerebral cortex open the possibility of testing novel hypotheses experimentally, and thus eventually extending the results to translational efforts aimed at new, more effective treatments, early diagnosis, and prevention.