Creighton H. Phelps

The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease

The National Institute on Aging and the Alzheimers Association charged a workgroup with the task of revising the 1984 criteria for Alzheimers disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all‐cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

The pathophysiological process of Alzheimers disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimers Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease‐modifying therapies may be most efficacious.

National Institute on Aging–Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimers disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre‐clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP‐43 inclusions, and recommend standard approaches for the workup of cases and their clinico‐pathologic correlation.

Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

Criteria for the clinical diagnosis of Alzheimers disease (AD) were established in 1984. A broad consensus now exists that these criteria should be revised to incorporate state‐of‐the‐art scientific knowledge.

National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach

We present a practical guide for the implementation of recently revised National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an “ABC” score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.

Utility of the Apolipoprotein E Genotype in the Diagnosis of Alzheimer's Disease

BACKGROUND The epsilon4 allele of the gene encoding apolipoprotein E (APOE) is strongly associated with Alzheimers disease, but its value in the diagnosis remains uncertain. METHODS We reviewed clinical diagnoses and diagnoses obtained at autopsy in 2188 patients referred to 1 of 26 Alzheimers disease centers for evaluation of dementia. The sensitivity and specificity of the clinical diagnosis or the presence of an APOE epsilon4 allele were calculated, with pathologically confirmed Alzheimers disease used as the standard. The added value of the APOE genotype was estimated with pretest and post-test probabilities from multivariate analyses to generate receiver-operating-characteristic curves plotting sensitivity against the false positive rate. RESULTS Of the 2188 patients, 1833 were given a clinical diagnosis of Alzheimers disease, and the diagnosis was confirmed pathologically in 1770 patients at autopsy. Sixty-two percent of patients with clinically diagnosed Alzheimers disease, as compared with 65 percent of those with pathologically confirmed Alzheimers disease, had at least one APOE epsilon4 allele. The sensitivity of the clinical diagnosis was 93 percent, and the specificity was 55 percent, whereas the sensitivity and specificity of the APOE epsilon4 allele were 65 and 68 percent, respectively. The addition of information about the APOE genotype increased the overall specificity to 84 percent in patients who met the clinical criteria for Alzheimers disease, although the sensitivity decreased. The improvement in specificity remained statistically significant in the multivariate analysis after adjustment for differences in age, clinical diagnosis, sex, and center. CONCLUSIONS APOE genotyping does not provide sufficient sensitivity or specificity to be used alone as a diagnostic test for Alzheimers disease, but when used in combination with clinical criteria, it improves the specificity of the diagnosis.

NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease

In 2011, the National Institute on Aging and Alzheimers Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimers disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimers Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimers Association Research Framework, Alzheimers disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six‐stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker‐based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker‐based research should not be considered a template for all research into age‐related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β‐amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

Recommendations of the Alzheimer's Disease–Related Dementias Conference

The National Alzheimers Project Act, signed into law in 2011, mandates a National Plan to Address Alzheimers Disease that is updated annually. In the Plan, the term Alzheimer disease includes not only Alzheimer disease (AD) proper, but also several specified related dementias, namely, frontotemporal, Lewy body, vascular, and mixed dementia. In response to a specific action item in the 2012 National Plan, the National Institute of Neurological Disorders and Stroke, in collaboration with the National Institute on Aging, convened panels of experts and conducted a 2-day public conference to develop research priorities and timelines for addressing Alzheimer disease–related dementias (ADRD) in 5 topic areas: multiple etiology dementias, health disparities, Lewy body dementias including dementia with Lewy bodies and Parkinson disease dementia, frontotemporal dementia and related tauopathies, and vascular contributions to ADRD. By design, the product was up to 8 prioritized research recommendations in each topic area including estimated timelines from when work on a recommendation is started to completion or to full implementation of an ongoing activity, and recognition of shared research themes across recommendations. These included increased education and training of both researchers and health care professionals, addressing health disparities, fundamental neurobiology research, advanced diagnostics, collaborative biosample repositories, and a focus on developing effective interventions to prevent or treat ADRD by the year 2025 as targeted by the National Plan.

A roadmap for the prevention of dementia: The inaugural Leon Thal Symposium

AD research has exploded during the last 20 years, resulting in the identification of numerous possible pathogenic pathways and targets for intervention. Accompanying this mechanistic research, neuropathologic and imaging studies have revealed that the pathogenic process begins long before the first symptoms appear and that modifying the disease process, in contrast to treating symptoms, might likewise require intervention long before the disease becomes evident. The drug development and regulatory processes, however, have for the most part remained focused on treating symptoms rather than preventing disease or intervening in its progression. The traditional phase I, II, and III trials follow a common pathway, evaluating first safety and tolerability, followed by dose finding and early effectiveness, and culminating in efficacy trials designed to demonstrate that a drug is safe and has a beneficial clinical effect. This model, however, is not appropriate for evaluating preventive or disease-modifying treatments, where the clinical benefits might be so subtle and far into the future as to be unmeasurable within a reasonable period of time. Multiple, interrelated barriers to drug development The barriers to developing preventive therapies span scientific, structural, business, and economic issues. Although it is clear that the disease process that eventually results in neurodegeneration and dementia in AD begins early, the exact nature and timing of these early steps are not known. AD might even represent the culmination of a neurodevelopmental process that begins at birth; or it might be a reflection of the normal aging process that is accelerated in some people for unknown reasons. The absence of a complete animal model of the disease (as opposed to partial models of selective pathologies) has certainly dampened the discovery process. A better understanding of disease progression in the earliest stages should also lead to the identification of novel therapeutic targets for preventing disease. The answers to these questions will emerge only through increased efforts to understand the basic biology of AD and neurodegeneration, including greater reliability in identifying early/prodromal AD, cognitive measures that are sensitive to change in mild disease, and the effect of changing lifestyles, medications, and lifestyle adaptations as management of mild dementia undergoes further development. This will require support for very long-term longitudinal studies, yet inadequate funding for basic science has stymied progress in this fundamental area. In fact, although the burden to society from AD has increased steadily since 1990, funding for AD research has remained flat. Clearly, new funding streams need to be established to ensure progress in both basic and applied research. As the drug development process moves from the basic science laboratories into clinical trials, infrastructural and regulatory barriers, along with different economic considerations, become paramount. Key players at this stage of the process include pharmaceutical companies, the Food and Drug Administration (FDA), and clinical trial sites. Although drug development in general is risky, expensive, and time-consuming, developing preventive treatments increases the challenges many fold. As a result, demonstrating effectiveness in preventing a disease might require such lengthy trials that the patent life on a drug will be exceeded. Moreover, at this time, methods for designing and implementing prevention trials, including how to identify at-risk subjects and how to assess outcome for those trials, have not been fully established. Responding to these multiple challenges will require flexibility and cooperation on the part of all stakeholders: clinicians, researchers, regulatory agencies, federal and private funders, Congress, pharmaceutical companies, and the public. A comprehensive strategic response to this challenge will require consideration of how to manage the risks that each of these stakeholders face. But the risk of not developing such a strategy is far greater in terms of the public health and economic impact.

Revision of the criteria for Alzheimer's disease: A symposium

The current criteria for classification of Alzheimers disease (AD) have deficiencies that limit drug development, research, and practice. The current standard for the clinical diagnosis of AD, the National Institute of Neurological and Communicative Disorders and Stroke (now known as the National Institute of Neurological Disorders and Stroke), and the Alzheimers Disease and Related Disorders Association (now known as the Alzheimers Association) criteria, are nearly 25 years old and have not been revised to incorporate advances in the epidemiology and genetics of AD, studies of clinicopathologic correlations and recent studies of potential diagnostic biomarkers. In a very real sense our ability to diagnose AD with a very high level of certainty has outpaced our current diagnostic criteria. The Alzheimers Association Research Roundtable convened a meeting in April 2009 to discuss new data and technologies that could, with further development, enable improvements in the clinical diagnosis of AD, especially in its earliest and mildest stages. This meeting reviewed the current standards for detecting and defining the clinical presentation of AD and discussed areas that could contribute to earlier and more accurate definitive clinical diagnosis. These included clinical, neuropsychological, and other performance‐based assessments, genetic contributions, and biochemical and neuroimaging biomarkers that could reflect AD pathology and lead to better ascertainment of AD, mild cognitive impairment, and presymptomatic AD.