Alzheimer’s disease (AD) is a slowly progressing disorder in which pathophysiological abnormalities, detectable in vivo by biomarkers, precede overt clinical symptoms by many years to decades. Five ...AD biomarkers are sufficiently validated to have been incorporated into clinical diagnostic criteria and commonly used in therapeutic trials. Current AD biomarkers fall into two categories: biomarkers of amyloid-β plaques and of tau-related neurodegeneration. Three of the five are imaging measures and two are cerebrospinal fluid analytes. AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping manner. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. In this Review, we discuss several time-dependent models of AD that take into consideration varying age of onset (early versus late) and the influence of aging and co-occurring brain pathologies that commonly arise in the elderly.
Jack and Holtzman review the major biomarkers of Alzheimer’s disease and relate them to specific pathophysiological processes. They also outline a framework for temporal evolution of AD biomarkers in the context of both early- and late-onset disease.
Structural imaging based on magnetic resonance is an integral part of the clinical assessment of patients with suspected Alzheimer dementia. Prospective data on the natural history of change in ...structural markers from preclinical to overt stages of Alzheimer disease are radically changing how the disease is conceptualized, and will influence its future diagnosis and treatment. Atrophy of medial temporal structures is now considered to be a valid diagnostic marker at the mild cognitive impairment stage. Structural imaging is also included in diagnostic criteria for the most prevalent non-Alzheimer dementias, reflecting its value in differential diagnosis. In addition, rates of whole-brain and hippocampal atrophy are sensitive markers of neurodegeneration, and are increasingly used as outcome measures in trials of potentially disease-modifying therapies. Large multicenter studies are currently investigating the value of other imaging and nonimaging markers as adjuncts to clinical assessment in diagnosis and monitoring of progression. The utility of structural imaging and other markers will be increased by standardization of acquisition and analysis methods, and by development of robust algorithms for automated assessment.
Breakthroughs in the development of highly accurate fluid and neuroimaging biomarkers have catalysed the conceptual transformation of Alzheimer disease (AD) from the traditional clinical ...symptom-based definition to a clinical-biological construct along a temporal continuum. The AT(N) system is a symptom-agnostic classification scheme that categorizes individuals using biomarkers that chart core AD pathophysiological features, namely the amyloid-β (Aβ) pathway (A), tau-mediated pathophysiology (T) and neurodegeneration (N). This biomarker matrix is now expanding towards an ATX(N) system, where X represents novel candidate biomarkers for additional pathophysiological mechanisms such as neuroimmune dysregulation, synaptic dysfunction and blood-brain barrier alterations. In this Perspective, we describe the conceptual framework and clinical importance of the existing AT(N) system and the evolving ATX(N) system. We provide a state-of-the-art summary of the potential contexts of use of these systems in AD clinical trials and future clinical practice. We also discuss current challenges related to the validation, standardization and qualification process and provide an outlook on the real-world application of the AT(N) system.
The findings substantially altered understanding of the natural history of Alzheimer's disease and have been summarised in a temporal model.4 Amyloid PET becomes abnormal before neocortical tau PET ...signal appears. β-amyloidosis seems to promote or facilitate the spread of tauopathy. Fluid phosphorylated tau biomarkers become abnormal close-in-time or slightly after onset of abnormal amyloid PET.6 This entire process can extend over 20 or more years.7 An updated model of the temporal evolution of biomarkers and cognitive impairment is shown in the figure.4 Plasma biomarkers have been the most important development in Alzheimer's disease diagnostics in the past several years. ...over the past two decades, GWAS studies have uncovered many loci associated with increased risk of clinically defined late-onset Alzheimer's disease, but with smaller effect size, lower population prevalence, or both compared with APOE4.15 These studies point to the importance of the immune response, endocytosis, lipid metabolism, and other pathways in addition to amyloid β and tau in the pathogenesis of Alzheimer's disease. Active disease modifying trials include both symptomatic and preclinical19 cohorts and involve biologicals or small molecules.20 In addition to those targeting amyloid β, trials targeting tau phosphorylation, aggregation and propagation, inflammation, neuroprotection, and other facets of the Alzheimer's disease pathway are underway or in the planning stages.20 Defining the optimal roles for different classes of biomarkers (plasma, CSF, and PET) in clinical trials and in clinical practice will continue to be an important research area.
Alzheimer disease (AD) is one of, if not the most, feared diseases associated with aging. The prevalence of AD increases exponentially with age after 60 years. Increasing life expectancy coupled with ...the absence of any approved disease-modifying therapies at present position AD as a dominant public health problem. Major advances have occurred in the development of disease biomarkers for AD in the past 2 decades. At present, the most well-developed AD biomarkers are the cerebrospinal fluid analytes amyloid-β 42 and tau and the brain imaging measures amyloid positron emission tomography (PET), fluorodeoxyglucose PET, and magnetic resonance imaging. CSF and imaging biomarkers are incorporated into revised diagnostic guidelines for AD, which have recently been updated for the first time since their original formulation in 1984. Results of recent studies suggest the possibility of an ordered evolution of AD biomarker abnormalities that can be used to stage the typical 20-30-year course of the disease. When compared with biomarkers in other areas of medicine, however, the absence of standardized quantitative metrics for AD imaging biomarkers constitutes a major deficiency. Failure to move toward a standardized system of quantitative metrics has substantially limited potential diagnostic usefulness of imaging in AD. This presents an important opportunity that, if widely embraced, could greatly expand the application of imaging to improve clinical diagnosis and the quality and efficiency of clinical trials.
In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's ...disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's 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 Alzheimer's Association Research Framework, Alzheimer's 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.
Basic research advances in recent years have furthered our understanding of the natural history of Alzheimer's disease (AD). It is now recognized that pathophysiological changes begin many years ...prior to clinical manifestations of disease and the spectrum of AD spans from clinically asymptomatic to severely impaired. Defining AD purely by its clinical presentation is thus artificial and efforts have been made to recognize the disease based on both clinical and biomarker findings. Advances with biomarkers have also prompted a shift in how the disease is considered as a clinico-pathophysiological entity, with an increasing appreciation that AD should not only be viewed with discrete and defined clinical stages, but as a multifaceted process moving along a seamless continuum. Acknowledging this concept is critical to understanding the development process for disease-modifying therapies, and for initiating effective diagnostic and disease management options. In this article, we discuss the concept of a disease continuum from pathophysiological, biomarker, and clinical perspectives, and highlight the importance of considering AD as a continuum rather than discrete stages. While the pathophysiology of AD has still not been elucidated completely, there is ample evidence to support researchers and clinicians embracing the view of a disease continuum in their study, diagnosis, and management of the disease.
Objective:
A workgroup commissioned by the Alzheimer's Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We ...performed a preliminary assessment of these guidelines.
Methods:
We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis, and 18fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cutpoints. A group of 450 cognitively normal (CN) subjects from a population‐based sample was used to develop cognitive cutpoints and to assess population frequencies of the different preclinical AD stages using different cutpoint criteria.
Results:
The new criteria subdivide the preclinical phase of AD into stages 1 to 3. To classify our CN subjects, 2 additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected non‐AD pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cutpoints corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0, 16% stage 1, 12 % stage 2, 3% stage 3, and 23% SNAP.
Interpretation:
This cross‐sectional evaluation of the NIA‐AA criteria for preclinical AD indicates that the 1–3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population‐based sample, leaving only 3% unclassified. Future longitudinal validation of the criteria will be important ANN NEUROL 2012;
The ability to define neuronal α-synuclein disease on the basis of its biology rather than its syndromic presentation follows from the development of a new enabling technology—accurate neuronal ...α-synuclein seed amplification assays in CSF. In addition to a biological definition, Simuni and colleagues1 propose an integrated staging system (neuronal α-synuclein disease integrated staging system; NSD-ISS) that has close parallels to the staging in the 2018 NIA-AA research framework.4 Biological staging (or ATN biomarker profiles) in the NIA-AA research framework was based on the concept that a characteristic sequence of pathophysiological events exists that can be captured by biomarkers. Another recent advancement in the Alzheimer's disease field is the development of plasma biomarkers, some of which have diagnostic accuracy equivalent to approved CSF assays.8–10 The convergence of high-quality plasma diagnostic assays, which are far more accessible than PET or CSF, with approved disease targeted therapeutics is projected to transform patient care for Alzheimer's disease.
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