Elsevier

The Lancet Neurology

Volume 9, Issue 11, November 2010, Pages 1118-1127
The Lancet Neurology

Position Paper
Revising the definition of Alzheimer's disease: a new lexicon

https://doi.org/10.1016/S1474-4422(10)70223-4Get rights and content

Summary

Alzheimer's disease (AD) is classically defined as a dual clinicopathological entity. The recent advances in use of reliable biomarkers of AD that provide in-vivo evidence of the disease has stimulated the development of new research criteria that reconceptualise the diagnosis around both a specific pattern of cognitive changes and structural/biological evidence of Alzheimer's pathology. This new diagnostic framework has stimulated debate about the definition of AD and related conditions. The potential for drugs to intercede in the pathogenic cascade of the disease adds some urgency to this debate. This paper by the International Working Group for New Research Criteria for the Diagnosis of AD aims to advance the scientific discussion by providing broader diagnostic coverage of the AD clinical spectrum and by proposing a common lexicon as a point of reference for the clinical and research communities. The cornerstone of this lexicon is to consider AD solely as a clinical and symptomatic entity that encompasses both predementia and dementia phases.

Introduction

Historically, Alzheimer's disease (AD) has been conceptualised as a “dual clinicopathological entity”, which to be fully ascertained requires (1) a clinical phenotype typically centred on the presence of a progressive dementia that includes episodic memory impairment as a defining feature and involvement of other cognitive domains or skills, and (2) specific neuropathological changes that usually include intraneuronal (neurofibrillary tangles) and extracellular parenchymal lesions (senile plaques), which are often accompanied by synaptic loss and vascular amyloid deposits.1, 2 Because neuropathological investigations cannot be done during life (except in very limited cases by brain biopsy), AD has evolved into a predominantly clinical entity with a probabilistic diagnosis (“probable AD”).3 In parallel, the term AD is used by neurobiologists and neuropathologists with reference to this specific pattern of neuropathological changes. This dichotomy in the use of AD to refer to either the clinical or the neuropathological entity is a potential source of confusion, particularly in light of repeated reports that pathological changes (“Alzheimer's pathology”) can exist without the concomitant clinical manifestations of AD.4, 5

The incremental growth of scientific knowledge around the pathogenic events and course of AD has significantly advanced our view of the disease and its defining boundaries. In 2007, the International Working Group for New Research Criteria for the Diagnosis of AD proposed a new diagnostic framework,6 intended to move beyond the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association (NINCDS–ADRDA) criteria.3 According to these new research criteria, the diagnosis of AD is made when there is both clinical evidence of the disease phenotype and in-vivo biological evidence of Alzheimer's pathology. By relying on the specific clinical and biological features of the disease, the newly proposed algorithm permits diagnosis of AD with a high level of accuracy, even at the stage of earliest clinical manifestations (prodromal stage).

Although successfully stimulating scientific discussion, the proposal of a “dual clinicobiological entity” that can be diagnosed during life also raises new questions about the definition of AD. For example, this framework did not initially address the nosology of AD-related states if the defining clinicobiological duality is not present. Additionally, conditions still to be considered within the new research criteria framework include the nosological classification of clinically asymptomatic individuals who are positive for biomarkers of Alzheimer's pathology, clinically symptomatic individuals without evidence of biomarker findings, or those with atypical features (atypical AD). There are now increasingly well recognised atypical presentations that include non-amnestic focal cortical syndromes, such as progressive non-fluent aphasia,7 logopenic aphasia,8 and posterior cortical atrophy,9 that are confirmed neuropathologically as being AD.

The aim of this Paper is to advance the new research criteria initiative by providing a companion lexicon wherein the different entities and concepts related to AD are defined and updated. This lexicon for AD is primarily intended to serve the research community by providing a framework of the disease that covers its full spectrum, and which should be used for research protocols and clinical trials directed at early intercession in the pathogenic cascade of the disease. The potential to test disease-modifying interventions adds urgency to the need for such a shared lexicon. The secondary aim is to provide clinicians with a clear view of this evolving field in which use of biomarkers is advancing and might reach regulatory qualification and approval in the foreseeable future. These dual aims are intended to keep the research and clinical view of the disease from becoming too widely separated.

Section snippets

Methods

In 2007, the International Working Group published the framework for new research criteria for AD.6 Subsequently, the International Working Group has convened annual meetings to advance this initiative, including considerations of how the new research criteria might be further developed and validated. In July, 2008, more than 50 participants with academic or pharmaceutical experience, primarily from Europe and North America, participated in a meeting during the International Conference on

Alzheimer's disease

Currently, clinicians use the term AD to refer to a clinical entity that typically presents with a characteristic progressive amnestic disorder with subsequent appearance of other cognitive, behavioural, and neuropsychiatric changes that impair social function and activities of daily living.1 The initial presentation can also be atypical, with non-amnestic focal cortical cognitive symptoms.9 In most cases, clinicians make this diagnosis of AD with varying degrees of confidence on the basis of

Alzheimer's pathology

For basic neuroscience and neuropathology researchers, AD refers to the pathological process that is defined by specific neuronal lesions including senile plaques and neurofibrillary tangles, and that is associated with neuronal loss, synaptic loss, and frequently with cerebral amyloid angiopathy.18 This pathological process might or might not become symptomatic during life.61, 62 For research and clinical purposes, we propose to refer to the underlying pathology of the disease at the genetic,

Preclinical states of Alzheimer's disease

There is growing interest in the long preclinical phase of AD.4, 31, 49, 62, 63 Within this lexicon, we distinguish two preclinical states of AD in which individuals are free of cognitive/behavioural symptoms, yet have either biomarker evidence of Alzheimer's pathology or a monogenic form of AD. We propose the term “asymptomatic at risk for AD” for individuals with biomarker evidence of Alzheimer's pathology, whereas “presymptomatic AD” is designated for carriers of monogenic forms of AD in

Prodromal (predementia) Alzheimer's disease

The term “prodromal AD” was introduced recently.72, 73 It characterises clinically affected patients who do not yet have dementia (predementia) and who are diagnosed to have AD on the basis of their clinical presentation and supportive evidence of Alzheimer's pathology from biomarkers. Prodromal AD should not be confused with preclinical AD. Prodromal AD describes a symptomatic disease phase, no matter how early, whereas preclinical AD describes the preceding asymptomatic state. The new

Alzheimer's disease dementia

It might still be meaningful to identify the dementia threshold as a severity milestone in the course of the disease with foreseeable clear economic and social implications.75 The transition to dementia predictably adds a set of management issues for clinicians to address, including those related to patient autonomy such as driving, financial capacity, and those related to caregiving. Given this transitional significance, the time to Alzheimer's dementia from its prodromal stage might be a

Typical Alzheimer's disease

The careful studies of Braak and Braak77 and Delacourte and colleagues78 have established the typical natural history of regional brain neuropathology and lesion patterns of AD, for which there is initial neurofibrillary involvement of the entorhinal cortex, the hippocampus, and related medial temporal structures, and which subsequently spreads to the neocortical association areas. This pathway of regional neuropathology correlates with the typical pattern of the cognitive changes of AD in

Atypical Alzheimer's disease

There are well defined clinical phenotypic variant presentations of AD that do not follow the typical pattern described above. These include non-amnestic focal cortical syndromes, such as primary progressive non-fluent aphasia, logopenic aphasia, posterior cortical atrophy,9 and frontal variant AD.80, 81 With the advent of biomarkers providing in-vivo confirmation of Alzheimer's pathology, it is now possible to include these clinical disorders as atypical AD if there is such biomarker support.55

Mixed Alzheimer's disease

Mixed AD is a diagnostic confound representing the co-occurrence of Alzheimer's pathology with other biological causes of cognitive decline, typically cerebrovascular disease or Lewy body pathology (panel). These comorbid conditions might present as overlapping clinical phenotypes of disease. Mixed pathologies are highly prevalent in elderly community-dwelling adults, and the contribution of co-occurring diseases to cognitive deterioration needs to be considered in any diagnostic scheme.72, 74

Mild cognitive impairment

MCI is a heterogeneous condition characterised by mild cognitive changes associated with various underlying aetiologies.93 The term MCI has therefore included some patients in the symptomatic prodromal phase of AD. Because patients with prodromal AD are now reclassified by their aetiology, they are no longer included within an MCI grouping. In the absence of any specifications of the memory profile and of any reference to specific biomarkers, MCI or amnestic MCI remains a syndromic

Conclusions

The value of these definitions is their potential application in clinical trials of disease-modifying drugs. Individuals identified as “asymptomatic at risk for AD” or “presymptomatic AD” might be enrolled in trials aimed at delaying the onset of clinical signs. Patients with prodromal AD could be included in trials of drugs targeting progression to more severe stages of AD (AD dementia). Uniformity of definitions will assist in constructing trial populations and comparing results across

References (93)

  • B Dubois et al.

    Amnestic MCI or prodromal Alzheimer's disease?

    Lancet Neurol

    (2004)
  • CP Ferri et al.

    Global prevalence of dementia: a Delphi consensus study

    Lancet

    (2005)
  • L Parnetti et al.

    Cerebrospinal fluid biomarkers in Parkinson's disease with dementia and dementia with Lewy bodies

    Biol Psychiatry

    (2008)
  • I McKeith et al.

    Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study

    Lancet Neurol

    (2007)
  • JL Cummings

    Alzheimer's disease

    N Engl J Med

    (2004)
  • HW Querfurth et al.

    Alzheimer's disease

    N Engl J Med

    (2010)
  • G McKhann et al.

    Clinical diagnosis of Alzheimer's disease: report of the NINCDS–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease

    Neurology

    (1984)
  • DA Bennett et al.

    Neuropathology of older persons without cognitive impairment from two community-based studies

    Neurology

    (2006)
  • DS Knopman et al.

    Neuropathology of cognitively normal elderly

    J Neuropathol Exp Neurol

    (2003)
  • V Deramecourt et al.

    Prediction of pathology in primary progressive language and speech disorders

    Neurology

    (2010)
  • J Cummings

    Primary progressive aphasia and the growing role of biomarkers in neurological diagnosis

    Ann Neurol

    (2008)
  • S Alladi et al.

    Focal cortical presentations of Alzheimer's disease

    Brain

    (2007)
  • AM Fagan et al.

    Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans

    Ann Neurol

    (2006)
  • WJ Jagust et al.

    Relationships between biomarkers in aging and dementia

    Neurology

    (2009)
  • MA Mintun et al.

    [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease

    Neurology

    (2006)
  • K Buerger et al.

    CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease

    Brain

    (2006)
  • CM Clark et al.

    Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses?

    Arch Neurol

    (2003)
  • MD Ikonomovic et al.

    Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease

    Brain

    (2008)
  • D Strozyk et al.

    CSF Aβ 42 levels correlate with amyloid-neuropathology in a population-based autopsy study

    Neurology

    (2003)
  • T Tapiola et al.

    Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain

    Arch Neurol

    (2009)
  • Consensus recommendations for the postmortem diagnosis of Alzheimer's disease

    Neurobiol Aging

    (1997)
  • K Blennow et al.

    Cerebrospinal fluid and plasma biomarkers in Alzheimer disease

    Nat Rev Neurol

    (2010)
  • H Hampel et al.

    Correlation of cerebrospinal fluid levels of tau protein phosphorylated at threonine 231 with rates of hippocampal atrophy in Alzheimer disease

    Arch Neurol

    (2005)
  • N Mattsson et al.

    CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment

    JAMA

    (2009)
  • WE Klunk et al.

    Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B

    Ann Neurol

    (2004)
  • P Bourgeat et al.

    Beta-amyloid burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia

    Neurology

    (2010)
  • SR Choi et al.

    Preclinical properties of 18F-AV-45: a PET agent for Aβ plaques in the brain

    J Nucl Med

    (2009)
  • G Li et al.

    CSF tau/Aβ42 ratio for increased risk of mild cognitive impairment: a follow-up study

    Neurology

    (2007)
  • M Ewers et al.

    Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI

    Neurology

    (2007)
  • WJ Henneman et al.

    Baseline CSF p-tau levels independently predict progression of hippocampal atrophy in Alzheimer disease

    Neurology

    (2009)
  • JC Morris et al.

    Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease

    Arch Neurol

    (2009)
  • SM Resnick et al.

    Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB

    Neurology

    (2010)
  • D Holland et al.

    Subregional neuroanatomical change as a biomarker for Alzheimer's disease

    Proc Natl Acad Sci USA

    (2009)
  • MB Patwardhan et al.

    Alzheimer disease: operating characteristics of PET—a meta-analysis

    Radiology

    (2004)
  • JL Whitwell et al.

    MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study

    Neurology

    (2008)
  • LG Apostolova et al.

    Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps

    Arch Neurol

    (2006)
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