Toward a multi-dimensional formulation of the pathogenesis and pathophysiology of the Alzheimer dementia-like syndrome applicable to a variety of degenerative disorders and normal cognition

SummaryNeurodegenerative disorders constitute a set of heterogeneous conditions lacking a satisfactory unifying conceptual scheme. This situation is widely perceived as hampering progress in understanding them adequately in order to develop effective treatment and prevention, but there is no unanimously or even generally agreed upon solution to this dilemma. Here, we propose that progress in resolving this conundrum requires addressing in an integrated fashion multiple dimensions and scales of organization and (normal and disordered) function that include, but transcend the conventional levels of space, time, Molecular Biology/Biochemistry and Systems Neuroscience, among others. This approach must include also a revision of the nosological concepts that currently attempt to force pathophysiological and etiological explanations within a single domain (nowadays predominantly the Molecular/Biochemical) that have virtually always failed to deliver on titillating expectations based on relatively simple “atomizing” schemes focusing on one domain/level, while ignoring virtually all others. This multi-dimensional integrated approach is illustrated for the Alzheimer dementia-like syndrome taking advantage of the wealth of knowledge in several of the relevant domains, but is generally applicable to potentially the entire range of neurodegenerative disorders, and probably also to other aspects of normal and disordered cognition and behavior.