Perspective: Clinical relevance of the dichotomous classification of Alzheimer's disease biomarkers: Should there be a "gray zone"?

The 2018 National Institute on Aging and the Alzheimer's Association (NIA-AA) research framework recently redefined Alzheimer's disease (AD) as a biological construct, based on in vivo biomarkers reflecting key neuropathologic features. Combinations of normal/abnormal levels of three biomarker categories, based on single thresholds, form the AD signature profile that defines the biological disease state as a continuum, independent of clinical symptomatology. While single thresholds may be useful in defining the biological signature profile, we provide evidence that their use in studies with cognitive outcomes merits further consideration. Using data from the Alzheimer's Disease Neuroimaging Initiative with a focus on cortical amyloid binding, we discuss the limitations of applying the biological definition of disease status as a tool to define the increased likelihood of the onset of the Alzheimer's clinical syndrome and the effects that this may have on trial study design. We also suggest potential research objectives going forward and what the related data requirements would be.

Causes and Patterns of Dementia: An Update in the Era of Redefining Alzheimer's Disease.

The burden of dementia continues to increase as the population ages, with no disease-modifying treatments available. However, dementia risk appears to be decreasing, and progress has been made in understanding its multifactorial etiology. The 2018 National Institute on Aging-Alzheimer's Association (NIA-AA) research framework for Alzheimer's disease (AD) defines AD as a biological process measured by brain pathology or biomarkers, spanning the cognitive spectrum from normality to dementia. This framework facilitates interventions in the asymptomatic space and accommodates knowledge that many additional pathologies (e.g., cerebrovascular) contribute to the Alzheimer's dementia syndrome. The framework has implications for how we think about risk factors for "AD": Many commonly accepted risk factors are not related to AD pathology and would no longer be considered risk factors for AD. They may instead be related to other pathologies or resilience to pathology. This review updates what is known about causes, risk factors, and changing patterns of dementia, addressing whether they are related to AD pathology/biomarkers, other pathologies, or resilience.

Diagnostic Validity Comparison Between Criteria Based on CSF Alzheimer's Disease Biomarkers.

AIM: To compare the diagnostic validity of NIA-AA criteria, for AD CSF biomarkers, with our own new criteria. MATERIALS AND METHODS: Between 2008 and 2011, 170 patients with Mild Cognitive Impairment (MCI) were included. CSF levels of Aß1-42, T-tau, P-tau181, and ratios of T-tau/Aß1-42 and P-tau181/Aß1-42 were analyzed. In our criteria, we considered 3 or more abnormal variables indicative of a high likelihood of MCI due to AD. RESULTS: After a clinical follow-up of 4.5 ± 1.2 years, 44 patients remained stable, 95 developed AD, 15 other forms of dementia, 7 died and 9 received other diagnoses. Using the NIA-AA criteria and our own criteria, the diagnostic validity of the CSF biomarkers was 58% versus 85%, specificity 84% versus 72%, PPV 82% versus 79% and NPV 61% versus 79%. CONCLUSION: The inclusion of the ratios in diagnostic criteria increases sensitivity and NPV for the diagnosis of MCI due to AD.

Performance of a Condensed Protocol That Reduces Effort and Cost of NIA-AA Guidelines for Neuropathologic Assessment of Alzheimer Disease.

Concerns regarding resource expenditures have been expressed about the 2012 NIA-AA Sponsored Guidelines for neuropathologic assessment of Alzheimer disease (AD) and related dementias. Here, we investigated a cost-reducing Condensed Protocol and its effectiveness in maintaining the diagnostic performance of Guidelines in assessing AD, Lewy body disease (LBD), microvascular brain injury, hippocampal sclerosis (HS), and congophilic amyloid angiopathy (CAA). The Condensed Protocol consolidates the same 20 regions into 5 tissue cassettes at ∼75% lower cost. A 28 autopsy brain-retrospective cohort was selected for varying levels of neuropathologic features in the Guidelines (Original Protocol), as well as an 18 consecutive autopsy brain prospective cohort. Three neuropathologists at 2 sites performed blinded evaluations of these cases. Lesion specificity was similar between Original and Condensed Protocols. Sensitivities for AD neuropathologic change, LBD, HS, and CAA were not substantially impacted by the Condensed Protocol, whereas sensitivity for microvascular lesions (MVLs) was decreased. Specificity for CAA was decreased using the Condensed Protocol when compared with the Original Protocol. Our results show that the Condensed Protocol is a viable alternative to the NIA-AA guidelines for AD neuropathologic change, LBD, and HS, but not MVLs or CAA, and may be a practical alternative in some practice settings.

Mapping CSF biomarker profiles onto NIA-AA guidelines for Alzheimer's disease.

The National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines for Alzheimer's disease (AD) propose the categorization of individuals according to their biomarker constellation. Though the NIA-AA criteria for preclinical AD and AD dementia have already been applied in conjunction with imaging AD biomarkers, the application of the criteria using comprehensive cerebrospinal fluid (CSF) biomarker information has not been thoroughly studied yet. The study included a monocentric cohort with healthy (N = 41) and disease (N = 22) controls and patients with AD dementia (N = 119), and a multicentric sample with healthy controls (N = 116) and patients with AD dementia (N = 102). The CSF biomarkers ß-amyloid 1-42, total tau, and phosphorylated tau at threonine 181 were measured with commercially available assays. Biomarker values were trichotomized into positive for AD, negative, or borderline. In controls the presence of normal CSF profiles varied between 13.6 and 25.4 % across the studied groups, while up to 8.6 % of them had abnormal CSF biomarkers. In 40.3-52.9 % of patients with AD dementia, a typical CSF profile for AD was detected. Approximately 40 % of the potential biomarker constellations are not considered in the NIA-AA guidelines, and more than 40 % of participants could not be classified into the NIA-AA categories with distinct biomarker constellations. Here, a refined scheme covering all potential biomarker constellations is proposed. These results enrich the discussion on the NIA-AA guidelines and point to a discordance between clinical symptomatology and CSF biomarkers even in patients with full-blown AD dementia, who are supposed to have a clearly positive for AD neurochemical profile.

Application of the National Institute on Aging-Alzheimer's Association AD criteria to ADNI.

OBJECTIVE: We describe the operationalization of the National Institute on Aging-Alzheimer's Association (NIA-AA) workgroup diagnostic guidelines pertaining to Alzheimer disease (AD) dementia in a large multicenter group of subjects with AD dementia. METHODS: Subjects with AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with at least 1 amyloid biomarker (n = 211) were included in this report. Biomarker data from CSF Aß42, amyloid PET, fluorodeoxyglucose-PET, and MRI were examined. The biomarker results were assessed on a per-patient basis and the subject categorization as defined in the NIA-AA workgroup guidelines was determined. RESULTS: When using a requirement that subjects have a positive amyloid biomarker and single neuronal injury marker having an AD pattern, 87% (48% for both neuronal injury biomarkers) of the subjects could be categorized as "high probability" for AD. Amyloid status of the combined Pittsburgh compound B-PET and CSF results showed an amyloid-negative rate of 10% in the AD group. In the ADNI AD group, 5 of 92 subjects fit the category "dementia unlikely due to AD" when at least one neuronal injury marker was negative. CONCLUSIONS: A large proportion of subjects with AD dementia in ADNI may be categorized more definitively as high-probability AD using the proposed biomarker scheme in the NIA-AA criteria. A minority of subjects may be excluded from the diagnosis of AD by using biomarkers in clinically categorized AD subjects. In a well-defined AD dementia population, significant biomarker inconsistency can be seen on a per-patient basis.

Mild cognitive impairment: a subset of minor neurocognitive disorder?

The field of aging and dementia is increasingly preoccupied with identification of the asymptomatic phenotype of Alzheimer disease (AD). A quick glance at historical landmarks in the field indicates that the agenda and priorities of the field have evolved over time. The initial focus of research was dementia. In the late 1980s and 1990s, dementia researchers reported that some elderly persons are neither demented nor cognitively normal. Experts coined various terms to describe the gray zone between normal cognitive aging and dementia, including mild cognitive impairment. Advances made in epidemiologic, neuroimaging, and biomarkers research emboldened the field to seriously pursue the avenue of identifying asymptomatic AD. Accurate "diagnosis" of the phenotype has also evolved over time. For example, the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Task Force is contemplating to use the terms major and minor neurocognitive disorders. The six papers published in this edition of the journal pertain to mild cognitive impairment, which is envisaged to become a subset of minor neurocognitive disorders. These six studies have three points in common: 1) All of them are observational studies; 2) they have generated useful hypotheses or made important observations without necessarily relying on expensive biomarkers; and 3) Based on the new National Institute on Aging and the Alzheimer's Association guidelines, all the studies addressed the symptomatic phase of AD. Questionnaire-based observational studies will continue to be useful until such a time that validated biomarkers, be it chemical or neuroimaging, become widely available and reasonably affordable.

Ethical issues in Alzheimer's disease: an overview.

Alzheimer's disease (AD) accounts for the majority of dementia cases and leaves clinicians, patients, family members, caregivers, and researchers faced with numerous ethical issues that vary and evolve as a function of disease stage and severity. While the disclosure of a diagnosis of AD dementia is difficult enough, advances in the neurobiology of AD--embodied in the recent revisions to the AD diagnostic guidelines--have translated into an increasing shift toward the diagnosis being made in its pre-dementia stages, when patients have full insight into their prognosis. Genetic issues in AD are significant in the case of rare families with an early onset (before age 65) form of the disease, owing to the presence of deterministic mutations. While genetic testing for the apolipoprotein E (APOE) gene--a risk factor for sporadic AD--is widely debated, it may become necessary in the context of novel disease-modifying drugs. The current symptomatic drugs--cholinesterase inhibitors (CIs) and the NMDA receptor antagonist memantine--are relatively simple to use but their access is limited in many countries by economic considerations and therapeutic nihilism. Although their efficacy is modest, they influence the design of protocols for new drugs since placebo treatment in clinical trials involving patients with established dementia is rarely allowed beyond 3 months. Driving privileges are lost in the moderate stages of dementia, with this decision ideally reached using a standardized assessment algorithm. Physical restraints are still overused in moderate-to-severe stages, but the alternative non-pharmacological therapies and caregiver training programs are not yet fully validated using randomized studies. End-of-life care is slowly moving towards a palliative care approach similar to that for end-stage cancer. There will be new drugs in the near future, some of which will delay progression from prodromal stages to dementia, but their use will require careful stopping rules.

An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer 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 (18) fluorodeoxyglucose 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.

Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010.

The neuropathologic examination is considered to provide the gold standard for Alzheimer disease (AD). To determine the accuracy of currently used clinical diagnostic methods, clinical and neuropathologic data from the National Alzheimer's Coordinating Center, which gathers information from the network of National Institute on Aging (NIA)-sponsored Alzheimer Disease Centers (ADCs), were collected as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) between 2005 and 2010. A database search initially included all 1198 subjects with at least one UDS clinical assessment and who had died and been autopsied; 279 were excluded as being not demented or because critical data fields were missing. The final subject number was 919. Sensitivity and specificity were determined based on "probable" and "possible" AD levels of clinical confidence and 4 levels of neuropathologic confidence based on varying neuritic plaque densities and Braak neurofibrillary stages. Sensitivity ranged from 70.9% to 87.3%; specificity ranged from 44.3% to 70.8%. Sensitivity was generally increased with more permissive clinical criteria and specificity was increased with more restrictive criteria, whereas the opposite was true for neuropathologic criteria. When a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathologic diagnoses were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration, cerebrovascular disease, Lewy body disease and hippocampal sclerosis. When dementia was not clinically diagnosed as AD, 39% of these cases met or exceeded minimum threshold levels of AD histopathology. Neurologists of the NIA-ADCs had higher predictive accuracy when they diagnosed AD in subjects with dementia than when they diagnosed dementing diseases other than AD. The misdiagnosis rate should be considered when estimating subject numbers for AD studies, including clinical trials and epidemiologic studies.

Revised criteria for mild cognitive impairment may compromise the diagnosis of Alzheimer disease dementia.

OBJECTIVE: To evaluate the potential impact of revised criteria for mild cognitive impairment (MCI), developed by a work group sponsored by the National Institute on Aging and the Alzheimer's Association, on the diagnosis of very mild and mild Alzheimer disease (AD)dementia. DESIGN: Retrospective review of ratings of functional impairment across diagnostic categories. SETTING: Alzheimer's Disease Centers and the National Alzheimer's Coordinating Center. PARTICIPANTS: Individuals (N=17 535) with normal cognition,MCI, or AD dementia. MAIN OUTCOME MEASURES: The functional ratings of individuals with normal cognition, MCI, or AD dementia who were evaluated at Alzheimer's Disease Centers and submitted to the National Alzheimer's Coordinating Center were assessed in accordance with the definition of "functional independence" allowed by the revised criteria. Pairwise demographic differences between the 3 diagnostic groups were tested using t tests for continuous variables and 2 for categorical variables. RESULTS: Almost all (99.8%) individuals currently diagnosed with very mild AD dementia and the large majority(92.7%) of those diagnosed with mild AD dementia could be reclassified as having MCI with the revised criteria,based on their level of impairment in the Clinical Dementia Rating domains for performance of instrumental activities of daily living in the community and at home.Large percentages of these individuals with AD dementia also meet the revised "functional independence" criterion for MCI as measured by the Functional Assessment Questionnaire. CONCLUSIONS: The categorical distinction between MCI and milder stages of AD dementia has been compromised by the revised criteria. The resulting diagnostic overlap supports the premise that "MCI due to AD" represents the earliest symptomatic stage of AD.

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 Alzheimer's 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.

BACKGROUND: Criteria for the clinical diagnosis of Alzheimer's 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. METHODS: The National Institute on Aging (NIA) and the Alzheimer's Association sponsored a series of advisory round table meetings in 2009 whose purpose was to establish a process for revising diagnostic and research criteria for AD. The recommendation from these advisory meetings was that three separate work groups should be formed with each assigned the task of formulating diagnostic criteria for one phase of the disease: the dementia phase; the symptomatic, pre-dementia phase; and the asymptomatic, preclinical phase of AD. RESULTS: Two notable differences from the AD criteria published in 1984 are incorporation of biomarkers of the underlying disease state and formalization of different stages of disease in the diagnostic criteria. There was a broad consensus within all three workgroups that much additional work is needed to validate the application of biomarkers for diagnostic purposes. In the revised NIA-Alzheimer's Association criteria, a semantic and conceptual distinction is made between AD pathophysiological processes and clinically observable syndromes that result, whereas this distinction was blurred in the 1984 criteria. CONCLUSIONS: The new criteria for AD are presented in three documents. The core clinical criteria of the recommendations regarding AD dementia and MCI due to AD are intended to guide diagnosis in the clinical setting. However, the recommendations of the preclinical AD workgroup are intended purely for research purposes.

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 Alzheimer's 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 Alzheimer's 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.

The diagnosis of mild cognitive impairment 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 Alzheimer's Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer's disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.

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 Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's 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.