The complexities of the pathology-pathogenesis relationship in Alzheimer disease

Current pathogenic theories for Alzheimer disease (AD) and aging favor the notion that lesions and their constituent proteins are the initiators of disease due to toxicity. Whether this is because structural pathology is traditionally viewed as deleterious, and whether this, in turn, is a fundamental misinterpretation of the relationship between pathology and pathogenesis across the spectrum of chronic diseases, remains to be determined. As more and more detailed information about the biochemical constituents of AD lesions becomes available, it may also be argued that just as much knowledge of cellular physiology as pathophysiology has been gained. Indeed, essentially all major proteins in AD lesions are derived from molecular cascades, which are in turn highly conserved across cells, tissues, and species. Moreover, the lesions themselves are observed in the cognitively intact, and sometimes in large numbers, while major consensus criteria indicate that an extent of pathology is normal with advanced age. As the medical science community continues to pursue lesion targeting for therapeutic purposes, the notion that AD pathology is indicative of an active host response or environmental adaptation, and therefore a poor target, is becoming clearer. (C) 2014 Elsevier Inc. All rights reserved.