The publication of revised criteria/guidelines for the diagnosis of Alzheimer's disease (Dx-AD) in the current issue of Alzheimer's & Dementia is a momentous milestone in the prolonged history of efforts to characterize the distinct clinical-pathological features of a complex syndrome—Alzheimer's disease (AD). The amendments to the current criteria recommended by the National Institute on Aging (NIA)-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease represent significant progress in that endeavor by adding important new features that would enhance the precision and accuracy of differential diagnosis of this syndrome. These revisions promise to have a profound impact on the pace and direction of future research as well as the global effort to find a cure. Our field owes a great debt of gratitude to the members of the three workgroups, as well as to the NIA and the Alzheimer's Association, for their leadership in crafting the first significant revision of the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) criteria [1] of 1984. Much of what the NIA-Alzheimer's Association workgroups are recommending is a redefinition of AD to include 3 stages: 1) a dementia stage for which the original NINCDS/ADRDA and the revised National Institute on Aging/Alzheimer's Association criteria apply; 2) a mild cognitive impairment (MCI) stage where there are core criteria for MCI but only guidelines of how to relate MCI to AD after further research and validation of biomarkers; and 3) a preclinical stage where there are no criteria for diagnosis but, instead, presentation of a staging hypothesis for further research related to the use of biomarkers to identify people with changes in the brain consistent with those seen later in MCI and AD dementia. An important point for all three stages is that the workgroups have created a framework for research on the relationship of the underlying pathophysiology to the emergence of clinical symptoms. In addition, for MCI and AD dementia, basic diagnostic criteria for use in current clinical practice are presented. The purpose of this editorial is to provide a brief historic context to the significance of the proposed revisions to the Dx-AD criteria and offer recommendations for further action in the future concerning this "work-in-progress." One of the questions concerning this revision is—why there was a 27 years hiatus between the publication of the original criteria and current version? Perhaps the next reiterations of these criteria will occur at regular and shorter intervals. The issue of a long lag time between re-evaluation/revision of Dx-AD criteria is a serious matter for future progress in the field; however, this concern needs to be moderated in the context of early struggles to advance the field. Although the study of dementia has a 100-year history, systematic efforts to address the array of scientific and clinical challenges to differential diagnosis of AD syndrome is a relatively recent phenomenon. Thus, several hurdles had to be overcome before the 1984 NINCDS-ADRDA criteria as well as during the intervening period between 1984 and 2011 (e.g., the lack of validated assessment tools, the necessary infrastructure for systematic clinical/longitudinal studies). Historically, one of the early core issues for the field of dementia was the question of whether AD changes are simply an accentuation of normal senescence. Even today, this problem remains to be a critical challenge. The landmark investigations by Blessed et al [2] began to address this issue in late 1960s and set the stage for the subsequent efforts to distinguish brain changes owing to pathology from those associated with healthy aging. In the United States, the trend for integrating clinical and biological studies of dementia (i.e., clinico-pathological correlations) started to take shape a decade later in parallel with advances in neurochemistry, histology, electron microscopy, neuroanatomy, molecular biology, genetics, and imaging. The critical event that set the stage for this approach was the 1977 seminal workshop (published in 1978) organized by the NINCDS, NIA, and National Institute of Mental Health, chaired by Robert Katzman, Robert Terry, and Katherine Bick [3]. Subsequently, in 1978, the NIA began to build its extramural program on AD by focusing on developing the infrastructure and tools for such clinical-pathological studies. The institute placed high priority on developing, standardizing, and validating various assessment instruments, diagnostic procedures, as well as fostering the formulation of distinct diagnostic criteria for clinical workup and neuropathological evaluation [[4]–[6]]. These early efforts by NIA led to the creation of an array of quantitative measures of cognition. Other program initiatives, which promoted the validation of instruments for objective evaluation of symptoms, were critical preliminary steps in developing the capabilities of the field for systematic characterization of the AD syndrome. These early efforts to encourage the development and validation of the necessary tools and infrastructure for assessment of the disease took time, but also became the foundation for much of the current "routine clinical-workup," and set the "standard" for clinical staging methods as an essential element of clinical criteria. One of the other critical barriers for systematic "clinico-pathological studies" was the lack of widely agreed upon criteria for the neuropathological evaluation of putative cases of people with AD syndrome, as compared with healthy aging brains. This problem was addressed by a "Research Planning Workshop on Diagnosis of Alzheimer's Disease," organized by NIA in 1983 (published in 1985 [4]).The recommendations of this workshop led to several program initiatives that prepared the ground for the next 27 years of research on clinico-pathological correlations, as well as some of the issues covered by the current NIA-Alzheimer's Association Dx criteria presented in this issue. For example, the Neuropathology Panel of NIA's 1983 workshop on AD-Dx took the first step toward defining the minimum microscopic criteria necessary for histological diagnosis of AD. The Neurology Panel suggested that the term "Alzheimer Disease" be reserved for patients who show a compatible clinical course along with the histopathological and neurochemical changes associated with the disease. The panel also considered the problem of distinguishing AD from benign senescent forgetfulness (mild cognitive impairment) and non-AD-type dementia. Other topics and recommendations of this workshop included neuroimaging, biomarkers, molecular genetics, longitudinal studies, brain banks, establishment of family registries and pedigree studies, animal models, and the need for research on normal brain aging. Before 1984, in the absence of specific diagnostic criteria for AD, the Diagnostic and Statistical Manual of Mental Disorders (DSM-III/IV) criteria [7] for diagnosis of dementia had fulfilled the requirements of clinical research. Finally, this need was addressed with the dual publications of: (a) "NINCDS-ADRDA Diagnostic Criteria" [1] and (b) NIA's "Diagnosis of Alzheimer's Disease" [4]; these two corollary criteria specified not only inclusion/exclusion factors with three levels of confidence ("McKhann criteria" [1]) but also an objective quantitative measure for histopathological confirmations ("Khachaturian criteria" [4]—with its subsequent revisions [[8],[9]]). Several of the programs and initiatives launched by NIA during the period of 1978 to 2011 (e.g., Centers Program, Consortium to Establish a Registry for Alzheimer's Disease [CERAD], Alzheimer's Disease Clinical Studies [ADCS], Alzheimer's Disease Neuroimaging Initiative [ADNI]) were designed, in part, to enable the development and validation of quantitative objective assessment technologies and algorithms for earlier and earlier detection of the AD syndrome. For example, the "Alzheimer's Disease Patient Registry" Program was launched in 1986 to address the goal of developing standardized diagnostic assessments. This program included the CERAD led by Al Heyman and Gerda Fillenbarum, the Mayo Clinic Registry led by Len Kurland and Ron Peterson, the Seattle site led by Eric Larson, the Mon valley project with Lewis Kuller and Mary Ganguli, and Denis Evans's group in East Boston. The CERAD project was successful in establishing uniform methods for the diagnosis and assessment of AD because of the dedicated and effective leadership provided by Al Heyman and the cooperation of clinicians and investigators nationwide and worldwide. Overall, the Alzheimer's Disease Patient Registry program was instrumental not only in the development of assessment instruments/procedures for standardization but also in helping to refine the concept "mild cognitive impairment." During the last 27 years, the improvements in the accuracy of the clinical diagnosis have been remarkable. The procedures for clinical assessment and differential Dx-AD steadily advanced toward well-validated algorithms for identification of positive clinical phenotypes of the diseases. Early diagnosis has become one of the most important clinical accomplishments with profound implications for: (1) research, (2) establishing the prevalence of AD, (3) initiating treatment when it may have optimal benefit, and (4) understanding the pathobiology of the disease. There is a general consensus that many of the advances in diagnosis, treatment(s), care, and understanding the cause(s) would not have been possible without the creation of instruments, criteria, infrastructure, and programs that support interdisciplinary research. Some of the spectacular clinical and research strides are attributable in large measure to the NIA initiatives since 1978. Thus, the publication of these newly revised criteria by the NIA–Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease has not only written the coda for a prolonged history of scientific efforts to characterize the clinical features of dementia but it has also brought the field to the threshold of a new frontier—the struggle toward primary prevention [10]. The new challenges for the field are no less ambitious or difficult to overcome as compared with those that were confronted three decades ago when dementia was an obscure neurological condition confused with senility. However, the field cannot wait for another three decades for a re-evaluation of the protocols for characterizing the AD syndrome in its various stages of progression. Currently, there is growing recognition that the neurobiological processes associated with AD syndrome start many years before the appearance of any measurable clinical signs or impairments of function. Thus, the new challenge for formulating future revisions to the Dx-AD criteria is to move the bar for discriminating the "affected" from "unaffected" on into the unknown territory of identifying asymptomatic people at elevated risk for the disease in the preclinical stages. The primary Achilles' heel for the future revision of the criteria will be the accuracy or utility of current model of pathogenesis and conceptual model of the syndrome. The field is ready now to consider different conceptual models for neurodegenerative diseases (e.g., "System Failure" Model for Complex Disease of the Brain). The core premise for such a shift in thinking is based on the proposition that the expression of key clinical features in neurodegenerative diseases (e.g., impairments in memory, movement or mood) are a reflection of a systems failure, of a complex neural network, rather than due to a single etiologic factor. This type of a model for the pathogenesis of the disease requires a drastic shift in research and development priorities beyond the problems of protein cleavage and aggregation. Thus, the validation of such conceptual model, of a complex disease/syndrome such as AD, will rely on developing multiple strategies aimed at preserving/maintaining the functionality of the "system." In the case of AD the "system" could be defined by the synaptic functionality or viability of a neuronal network or global malfunction of well-defined anatomical structure. The operational framework for such a model does not rely on a single etiologic factor. Rather, this embedded-set model approach requires understanding the functional relationships among key components of a system and identifying approaches to optimize the functioning of the overall system by examining the character of its constitutive components. Present notions about the neurobiology of dementia, which have enjoyed nearly universal acceptance during the last three decades, have proven to be inadequate in providing effective targets for treating "complex disease." One explanation for the lackluster performance of current drug development paradigms might be the failure of the prevailing ideas about the pathogenesis of the disease to provide a complete account of relationship between the clinical and biological phenotypes of the disease. The current revision of the criteria was largely based on the prevailing conceptual model of dementia/AD, which is increasingly being questioned and found to be inadequate. Future revisions of the criteria, especially when intended to promote trials for prevention, will require the adoption of new thinking (or models) about the full spectrum of pathogenesis. The new models need to: 1) fully incorporate the temporal lag between the initiating pathological event and the first appearance of symptoms; 2) provide complete [or better] explanations for the biological underpinnings of the key clinical features of the disease (e.g., loss of memory and overall deterioration of cognitive functions); and 3) identify new or different therapeutic target.
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Zaven S. Khachaturian (2011) studied this question.
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