![]() ![]() ![]() Indeed, the most direct test of the pathology hypothesis, vaccine therapy, has led to pathology reversal at the cost of increased morbidity and mortality with no cognitive benefits. Unfortunately, focusing on AD pathogenesis through the narrow prism of “lesion = disease,” has not lead to a significant therapeutic advances. Such a focus is not surprising, since pathological lesions have been effective avenues to therapeutics for over two centuries. With each successive wave of technology, precision has increased, but the target – the pathological lesions or their surrogates – has remained essentially unchanged for those 100 years.Įven the hope of unbiased analysis through molecular genetics has disclosed genes that have all been related to AD through the pathology. Throughout this time, up to the present, the technology of the day continues to attempt to understand AD pathogenesis ( Table 1). Last year marked the centennial of the clinical pathological discovery of AD, a dementia characterized by two pathological lesions. As such, a fundamental re-organization of the thought processes surrounding the pathology of chronic diseases is paramount, and a more open-minded view of pathology by pathologists themselves, we believe, is necessary to fulfill the ultimate goal of providing useful information that would guide treatment efforts. Such concrete thinking, we believe, represents a fundamental misconception of the relationship between pathology and chronic disease, one that has been propagated over the decades as scientists perseverate on the latest technologies rather than the clinico-pathological entities themselves. Yet, studies addressing the pathogenesis of AD are dominated by the latter construct, something more akin to an acute infection than an age-related neurodegeneration, suggesting that removal of the microscopic lesion (infectious agent by analogy) will restore health. ![]() an adaptive response to a chronic process, or death. In contrast, the pathological changes of AD develop over years, and it remains an open question whether such changes mark a movement toward health, i.e. The structural changes of the disease are linked to processes at disequilibrium. Why is this distinction so important? The medicine-pathology partnership has made the most headway with acute disease (e.g., coronary artery thrombosis and myocardial infarction), where the body responds quickly and directly to a process that if not addressed rapidly leads to major morbidity and mortality. The pathologists' fascination with lesions, and in particular, lesions that can be visualized – in the case of AD, the senile plaque and neurofibrillary tangle – has proven a powerful and distracting a priori bias in his assessment of pathophysiology. At the root of the issue is the role of the pathologist, who may, in the setting of chronic diseases such as AD, assign too literal a meaning to the basic pathology. Here we consider the slow progress made in effectively understanding and healing Alzheimer disease (AD) by some of the most talented scientists of our time. This paradigm has been particularly successful in providing insights for treatment of acute diseases however, in the setting of chronic disease, where the relationship between basic pathology (typically end-stage) and pathophysiology is often misinterpreted, progress towards effective therapy has been slow, at best. ![]() The careful study of pathology has delivered an understanding of disease sufficient to guide effective treatment, and recognize ineffective treatment, so consequential to man's enhanced life expectancy in the past century. Since inception, pathology has served as the indispensable link between basic science and clinical disease, encompassing the defining of disease processes and mechanisms through observation of structural alterations, as well as hypothesis-driven experimentation. ![]()
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