www.thelancet.com/neurology Vol 9 November 2010
Lancet Neurol 2010; 9: 1118–27
October 11, 2010
See Refl ection and Reaction
Pierre & Marie Curie University,
Paris, Research Centre of the
Institute of the Brain and
Spinal Cord, Institute for
Memory and Alzheimer’s
Disease, UMR-S975, AP-HP,
Group, Paris, France
(Prof B Dubois MD,
M Sarazin MD, L C de Souza MD);
Division of Neurology,
University of British Columbia,
Vancouver, BC, Canada
(Prof H H Feldman MD,
C Jacova PhD); Department of
Neurology, Yale University,
New Haven, CT, USA
(H H Feldman); Bristol-Myers
Wallingford, CT, USA
(H H Feldman); UCLA-Easton
Alzheimer’s Disease Research
Center, Los Angeles, CA, USA
(J L Cummings MD);
Department of Neurology,
University of Virginia,
Charlottesville, VA, USA
(Prof S T DeKosky MD); INSERM
U897, Victor Segalen University
Bordeaux 2, Bordeaux, France
(P Barberger-Gateau MD);
Association for the
Development of Applied
(A Delacourte PhD); Istituto di
Ricovero e Cura a Carattere
Scientifi co (IRCCS)
Fatebenefratelli, Brescia, Italy
(Prof G Frisoni MD); Dementia
Research Centre, Department
Institute of Neurology,
University College London,
London, UK (Prof N C Fox MD,
Prof M Rossor MD); Department
of Neurosciences, University of
California, San Diego, CA, USA
(Prof D Galasko MD); McGill
Center for Studies in Aging,
Douglas Hospital, Montreal,
(Prof S Gauthier MD);
Department of Psychiatry,
Psychosomatic Medicine &
Revising the defi nition of Alzheimer’s disease: a new lexicon
Bruno Dubois, Howard H Feldman, Claudia Jacova, Jeff rey L Cummings, Steven T DeKosky, Pascale Barberger-Gateau, André Delacourte,
Giovanni Frisoni, Nick C Fox, Douglas Galasko, Serge Gauthier, Harald Hampel, Gregory A Jicha, Kenichi Meguro, John O’Brien, Florence Pasquier,
Philippe Robert, Martin Rossor, Steven Salloway, Marie Sarazin, Leonardo C de Souza, Yaakov Stern, Pieter J Visser, Philip Scheltens
Alzheimer’s disease (AD) is classically defi ned 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 specifi c pattern of cognitive changes and structural/biological
evidence of Alzheimer’s pathology. This new diagnostic framework has stimulated debate about the defi nition 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 scientifi c 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
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 defi ning
feature and involvement of other cognitive domains or
skills, and (2) specifi c neuropathological changes that
usually include intraneuronal (neurofi brillary tangles)
and extracellular parenchymal lesions (senile plaques),
which are often accompanied by synaptic loss and
vascular amyloid deposits.1,2 Because neuropatho logical
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 specifi c 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 scientifi c knowledge around
the pathogenic events and course of AD has signifi cantly
advanced our view of the disease and its defi ning
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 specifi c 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
Although successfully stimulating scientifi c discussion,
the proposal of a “dual clinicobiological entity” that can be
diagnosed during life also raises new questions about the
defi nition of AD. For example, this framework did not
initially address the nosology of AD-related states if the
defi ning clinicobiological duality is not present.
Additionally, conditions still to be considered within the
new research criteria framework include the nosological
classifi cation of clinically asymptomatic individuals who
are positive for biomarkers of Alzheimer’s pathology,
clinically symptomatic individuals without evidence of
biomarker fi ndings, 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-fl uent aphasia,7
logopenic aphasia,8 and posterior cortical atrophy,9 that are
confi rmed neuropathologically as being AD.
The aim of this Paper is to advance the new research
criteria initiative by providing a companion lexicon
wherein the diff erent entities and concepts related to AD
are defi ned 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 fi eld in which
use of biomarkers is advancing and might reach regulatory
qualifi cation 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.
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
www.thelancet.com/neurology Vol 9 November 2010 1119
University, Frankfurt, Germany
(Prof H Hampel MD);
Alzheimer’s Disease Center,
University of Kentucky,
Lexington, KY, USA
(G A Jicha MD); Department of
Neurology, Tohoku University
Graduate School of Medicine,
Sendai, Japan (K Meguro MD);
Wolfson Research Centre,
Institute for Ageing and
Health, Newcastle University,
Newcastle upon Tyne, UK
(J O’Brien DM); University of
Lille Nord de France (UDSL),
Equipes d’Accueil (EA) 2691,
Centre Hospitalier Universitaire
(CHU), Lille, France
(Prof F Pasquier MD); Centre
Mémoire de Ressources et de
Recherche CHU de Nice,
University of Nice-Sophia
Antipolis (UNSA), Nice, France
(Prof P Robert MD); Department
of Clinical Neurosciences,
Brown University, Providence,
RI, USA (Prof S Salloway MD);
Division, Taub Institute,
New York, NY, USA
(Prof Y Stern PhD); Department
of Psychiatry &
Centre Limburg, School of
Mental Health and
University Medical Centre,
(P J Visser MD); and Department
of Neurology and Alzheimer
Center, VU University Medical
Netherlands (P J Visser,
Prof P Scheltens MD)
Prof Bruno Dubois, Department
of Neurology, Salpêtrière
Hospital, 47 Boulevard de
l’Hôpital, 75013 Paris, France
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 (ICAD; Chicago, IL, USA) aimed at reviewing the
ongoing validation studies and aggregating data on the
new research criteria. On July 13, 2009, the International
Working Group hosted a featured research symposium at
the 2009 ICAD meeting (in Vienna, Austria) on how the
new criteria might be implemented within research
studies. Following on from the interest and discussions
generated at these meetings concerning the consequences
of the proposed conceptual framework, a clarifi cation and
a restatement of the defi nition of AD and related states
seemed necessary, and the International Working Group
recognised the timeliness of an initiative to further
elaborate a new lexicon.
This paper was developed through a three-step process:
(1) The leaders of the International Working Group (BD,
HHF, and PS) developed the broad conceptual coverage
and a comprehensive fi rst draft that was addressed to all
members of the International Working Group and to
other members who have been active since the 2007
publication (GF, HH, MS, LCdS). (2) Each member of
the International Working Group was asked to comment
and respond to the draft; all comments were collated and
the lead authors engaged in discussions within the group
by use of electronic communication reconciling diff ering
viewpoints to reach a fi nal consensus. This process led to
the broadening of several important areas, including the
inclusion of mixed AD and a fi rmer elaboration of
atypical AD. Finally, (3) the resulting manuscript was
further circulated to all coauthors for their fi nal validation
and interest in being part of the authorship of this
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 confi dence on the basis of their understanding
and weight of evidence for a typical or atypical phenotypic
presentation. To address this diagnostic uncertainty, the
1984 NINCDS–ADRDA criteria stipulated that diagnosis
of AD during life could only be “probable”, whereas a
“defi nite” diagnosis required
pathological confi rmation.3 Additionally, the diagnosis of
probable AD could be made only when the severity
threshold for dementia was reached and when other
causes of dementia had been excluded by biological and
neuroimaging examination. However, as noted, the term
AD has also been used by researchers to refer to the
pathological process alone. As a consequence, the original
clinicopathological duality traditionally inherent in the
term AD has gradually eroded.
Over the past two decades, it has become increasingly
possible to identify in-vivo evidence of the specifi c
neuropathology of AD by use of validated and disease-
specifi c biomarkers.10–12 This reliable identifi cation of AD
biomarkers supports a
conceptualisation and diagnosis of AD, because both
clinical and in-vivo biological manifestations of the
disease can now be integrated into the diagnosis.
Laboratory and neuroimaging biomarkers are very highly
correlated with the neuropathological lesions of AD.13–17
These biomarkers can be divided into pathophysiological
and topographical markers (table 1).
Pathophysiological markers correspond to the two
aetiological degenerative processes that characterise
Alzheimer’s pathology: the amyloidosis path to neuritic
plaques and the tauopathy path to neurofi brillary tangles.18
They include CSF measures of reduced concentrations of
amyloid β, increased total tau, and increased phospho-
tau,13,14,16,17,19–22 and amyloid PET scanning with Pittsburgh
compound B (PiB)15,23,24 or other radioligands (fl orbetaben,
¹⁸F-AV-45, etc).25,26 CSF biomarkers (low amyloid β and,
even more specifi cally, abnormal ratio of tau to amyloid β)27
are associated with very high rates of progression from
amnestic mild cognitive impairment (MCI) to AD
dementia,21,28 and have shown a consistently high
sensitivity and specifi city in predictive models.27–30 High
mean cortical binding values for PiB-PET are predictive
of cognitive decline and development of AD clinical signs
in cognitively normal elderly individuals.31,32 In-vivo
pathophysiological markers correlate very well with their
respective neuropathological lesions, including CSF
amyloid β and PiB-PET with senile plaques,15–17,19 and total
tau and phospho-tau with neurofi brillary tangles.13,14,17,19
Topographical markers are used to assess the less
specifi c and downstream brain changes that correlate
with the regional distribution of Alzheimer’s pathology
and include medial temporal lobe atrophy33–37 and reduced
glucose metabolism in temporo-parietal regions on
fl uorodeoxyglucose PET.38 These markers are valuable
major change in the
Cerebrospinal fl uid
Total tau, phospho-tau
Amyloid tracer uptake
Medial temporal atrophy
Table 1: Categorisation of the current, most-validated AD biomarkers
www.thelancet.com/neurology Vol 9 November 2010
indicators because structural brain changes accurately
map to the Braak stages of neurofi brillary tangle
deposition.39 These MRI and PET topographical markers
have been shown consistently to predict the development
of AD dementia in MCI cohorts,31,40–44 and to correlate
with disease severity.45,46
Among the pathophysiological and topographical
biomarkers, some have greater specifi city for Alzheimer’s
pathology and might provide a diff erent likelihood of an
AD diagnosis within a particular context. For example,
because medial temporal lobe atrophy can occur in
non-AD dementias47 or with ageing, a low CSF amyloid
β42 or a positive amyloid result on PET imaging might
have higher specifi city for the amyloidosis associated
with AD than would medial temporal lobe atrophy. In
2007, at the time of publication of the new research
criteria,6 there was no empirical basis for assigning
weightings to pathophysiological versus topographical
markers in the diagnosis of AD. Since then, understanding
of the timing of pathological events has increased, with
patho physiological changes preceding the topographical
changes associated with neurodegeneration.48 The latter
are more related to the emergence of cognitive
symptoms,49,50 although regional hypometabolism has
been shown with fl uorodeoxyglucose PET in asympto-
matic adults with genetic susceptibility for AD.51–54
According to this sequence of events, pathophysiological
markers could have diagnostic use at all disease stages,
including the preclinical stage, whereas topographical
markers would be more useful closer to the time when
the fi rst cognitive symptoms are manifest.
The availability of in-vivo biomarkers and their
correspondence with Alzheimer’s pathology form the basis
of the new research criteria, which were founded on a
clinicobiological defi nition.6 AD is now defi ned in vivo
with a diagnostic algorithm that begins with a characteristic
pattern of episodic memory impairment and then requires
supportive biomarkers that indicate the pathophysiology
or the topography of Alzheimer’s pathology. The presence
of dementia itself—the more severe form of AD—is not
required. The diagnosis of AD is made on the basis of both
clinical and biological evidence, with a very high level of
specifi city and predictive validity.55 Within this framework,
the designation of “probable” and “possible” AD is no
longer meaningful because of the use of reliable biomarkers
and the designation of “typical” and “atypical” AD.
The argument for defi ning AD as a clinicobiological
entity with a specifi ed clinical phenotype and in-vivo
evidence of the footprint of pathological changes has the
major advantage that there is no longer a reason to wait
until patients have developed full-blown dementia or to
exclude from diagnosis and treatment a large number of
patients who lack functional disability yet express the
disease. The diagnosis in turn can be uncoupled from a
particular threshold of severity, and there is no longer a
need to anchor the diagnosis of AD to a dementia
syndrome as is done today. Here, it is useful to refer to
Parkinson’s disease in cases in which the diagnosis does
not hinge on a level of severity (eg, when the patient is
bedridden), but on the presence of the earliest motor
symptoms (eg, a limited resting tremor of one hand). The
same should apply for AD, whereby the presence of a
distinctive episodic memory impairment pattern,6 together
with biological evidence on structural MRI,36 molecular
neuroimaging with PET,43 or CSF analysis,29 identifi es AD
with high accuracy at a symptomatic predementia stage.55
However, biomarkers are only supportive features in the
diagnostic framework, which is anchored to a core clinical
phenotype. Accordingly, AD has been identifi ed in patients
2 years before dementia with a specifi city of 92% using an
episodic memory test that assesses response to cueing.56
When CSF and volumetric MRI measures are added to
memory impairment, an extremely high degree of
specifi city has been reported.57–59 Use of the 2007 research
criteria for AD6 has been reported to capture the prodromal
phase of the disease,57,59,60 and supports the validity of a
diagnosis of AD before the occurrence of full-blown
dementia with functional impairment.
In summary, on the basis of this novel diagnostic
approach and on the evidence accumulated to date, we
propose that the term “Alzheimer’s disease” should refer
only to the in-vivo clinicobiological expression of the
disease and that it should encompass the whole spectrum
of its clinical course. Although prospective studies with
post-mortem verifi cation are needed to validate this new
proposal, the diagnosis of typical AD can now be made in
vivo with very high specifi city, given the specifi city of the
hippocampal pattern of memory loss with supportive
biomarkers. Accordingly, we anticipate that in the future a
single in-vivo marker or, more likely, a combination of
markers might be as reliable as neuropathological criteria
in establishing a defi nite diagnosis of AD. However, to
reach this point, the new clinicobiological defi nition needs
to be compared with the traditional dual neuropathological
diagnosis before establishing its validity as a new gold
standard. Furthermore, post-mortem examination remains
useful for the identifi cation of comorbid conditions,
alternative diagnoses (such as argyrophilic grain disease),
and atypical cases. In this lexicon, we propose that within
the framework provided by the new research criteria,
“defi nite AD” should be replaced with “neuropathologically
verifi ed AD”, whereby a post-mortem examination is used
to verify the clinicobiological diagnosis (panel).
For basic neuroscience and neuropathology researchers,
AD refers to the pathological process that is defi ned by
specifi c neuronal lesions including senile plaques and
neurofi brillary 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, molecular, or
www.thelancet.com/neurology Vol 9 November 2010 1121
cellular level as “Alzheimer’s pathology”. Alzheimer’s
pathology can be identifi ed post mortem in the absence of
any signifi cant evidence of cognitive or behavioural
changes in vivo.4 Because of lack of a clear understanding
of the relation between the neuropathological pattern of
the disease and its clinical occurrence, we believe that it
could be confusing to continue to use the term of AD for
both conditions, and we propose to distinguish between
AD expressed clinically and Alzheimer’s pathology, which
might or might not be clinically manifest. Neuro-
pathologically, the National Institute on Aging–Reagan
criteria of “intermediate likelihood” can occur at a
frequency of 10–36% in cognitively normal individuals
followed to autopsy.4 We thus propose to clearly separate
the clinical expression of the disease (AD) from the
underlying pathology (Alzheimer’s pathology; panel).
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 whom the
disease will invariably occur.
Asymptomatic at-risk state for AD
With the development of amyloid PET imaging, fi brillar
amyloid (one of the neuropathological hallmarks of the
disease) can be seen in a substantial proportion of ageing
individuals who are still cognitively normal and free of
symptoms (“asymptomatic at risk for AD”).12,61 Positive
PiB-PET scans are reported in 10–30% of older cognitively
normal controls.10,12,49,61,64 Similarly, decreased CSF
amyloid β42 has been shown in asymptomatic normally
functioning individuals.12,22 These individuals can be
defi ned as healthy, and might or might not later fulfi l
clinical AD diagnostic criteria. This evolution might
depend on individual susceptibility, including genetic
factors (eg, APOE genotype),1 other risk or protective
factors (eg, vascular factors, diet, etc), and comorbidities
(eg, diabetes). Recent data from follow-up studies indicate
that healthy individuals with abnormal CSF biomarkers
and PiB-PET positive changes develop AD at an increased
rate.27,31,32,65–67 Larger follow-up studies of asymptomatic
individuals with positive amyloid-β and tau biomarkers
will clarify their risk for AD. However, because individuals
who have been documented to be cognitively normal do
have evidence of senile plaques and neurofi brillary
tangles on autopsy,4 some of the people who have positive
PET amyloid tracers will clearly not go on to develop
cognitive impairment during their lifetimes. At this
point, as we cannot determine this group who will remain
asymptomatic, we will have to assume that they will be at
high risk of developing clinical symptoms, and would be
candidates for preventive therapies, depending on the
risk, expense, and side-eff ects of such therapies, and
Panel: A new lexicon for Alzheimer’s disease
Alzheimer’s disease (AD)
This diagnostic label is now restricted to the clinical disorder that starts with the onset
of the fi rst specifi c clinical symptoms of the disease, and encompasses both the
predementia and dementia phases. AD thus refers to the whole spectrum of the clinical
phase of the disease and is not restricted to the dementia syndrome. The diagnosis is
now established in vivo and relies on a dual clinicobiological entity that requires the
evidence of both specifi c memory changes and in-vivo markers of Alzheimer’s
pathology that can include: CSF amyloid β, total tau, and phospho-tau; retention of
specifi c PET amyloid tracers; medial temporal lobe atrophy on MRI; and/or temporal/
parietal hypometabolism on fl uorodeoxyglucose PET. The clinical phenotype can be
typical or atypical. Additionally, two diff erent stages might still be meaningful: a
prodromal and a dementia phase.
Prodromal AD (also called “predementia stage of AD”)
This term refers to the early symptomatic, predementia phase of AD in which (1) clinical
symptoms including episodic memory loss of the hippocampal type (characterised by a
free recall defi cit on testing not normalised with cueing) are present, but not suffi ciently
severe to aff ect instrumental activities of daily living and do not warrant a diagnosis of
dementia; and in which (2) biomarker evidence from CSF or imaging is supportive of the
presence of AD pathological changes. This phase is now included in the new defi nition
of AD. The term of prodromal AD might disappear in the future if AD is considered to
encompass both the predementia and dementia stages.
This term refers to the phase of AD during which cognitive symptoms are suffi ciently
severe to interfere with social functioning and instrumental activities of daily living, a
threshold that is considered to defi ne dementia in association with changes in episodic
memory and in at least one other cognitive domain. It might still be meaningful to
identify the dementia threshold for clinical trials or social/economic evaluations.
This term refers to the most common clinical phenotype of AD, which is characterised
by an early signifi cant and progressive episodic memory defi cit that remains dominant
in the later stages of the disease, and is followed by or associated with other cognitive
impairments (executive dysfunction, language, praxis, and complex visual processing
impairments) and neuropsychiatric changes. The diagnosis is further supported by one
or more in-vivo positive biomarkers of Alzheimer’s pathology.
This term refers to the less common and well characterised clinical phenotypes of the
disease that occur with Alzheimer’s pathology. These clinical syndromes include primary
progressive non-fl uent aphasia, logopenic aphasia, frontal variant of AD, and posterior
cortical atrophy. In the presence of one of these clinical presentations, the diagnosis of AD
is supported by in-vivo evidence of amyloidosis in the brain (with retention of specifi c
amyloid labelling radioligands) or in the CSF (with changes characteristic of Alzheimer’s
pathology in amyloid β, tau, and phospho-tau concentrations).
This term refers to patients who fully fulfi l the diagnostic criteria for typical AD and
additionally present with clinical and brain imaging/biological evidence of other
comorbid disorders such as cerebrovascular disease or Lewy body disease.
(Continues on next page)
www.thelancet.com/neurology Vol 9 November 2010
depending on the progress in determining which AD-
biomarker-positive healthy elderly people are unlikely to
develop clinical symptoms.
The discovery of specifi c biomarkers of the disease has
created new opportunities for a progressively earlier
recognition of the disease. The timing of pathological
events, as currently understood,49 confers primary
importance in this context to in-vivo markers of
amyloidosis. The borders between clinical AD and the
preclinical states of the disease might shift in the future
given continuing progress in the identifi cation of early
cognitive/behavioural changes (eg, decreased verbal
fl uency, attention defi cits, or executive dysfunction).
Recent data suggest that it might be possible to document
at an earlier stage the clinical onset of AD on the basis of a
precise clinical and/or neuropsychological investigation.68,69
However, it is likely that the earlier the diagnosis is made,
the less accurate it will be if no specifi c pattern of memory
or cognitive impairment has yet developed. For example,
patients who present with subjective isolated memory
complaints in the absence of objective evidence of a
specifi c memory defi cit, but with biomarker evidence
positive for brain amyloidosis, could be wrongly diagnosed
as having AD.22 For early disease recognition, there is a
clear need to characterise the clinical phenotype that is
highly specifi c for AD. This was the goal of the 2007
research diagnostic criteria.6 In the absence of specifi c AD
cognitive signs, we suggest that AD should not be
diagnosed, even if there is biological evidence of pathology,
but rather the possibility of categorising these patients as
having MCI should be considered.
For the asymptomatic state, because there is no
empirical basis yet to determine which biological changes
will be defi nitely associated with the further development
of the clinical symptoms of AD,49,61 we recommend that
this state should be referred to as “asymptomatic at-risk
state for AD”.
This term is applied to individuals who will develop AD
because they carry a fully penetrant genetic mutation, but
who are still free of symptoms of AD. At present, the only
case that fulfi ls this requirement is that of a carrier of a
familial genetic autosomal dominant mutation causative
of AD. These individuals are generally referred to as having
familial AD. To avoid any confusion with non-genetic
familial aggregation of the disease, we now propose to
introduce the term “monogenic AD” to characterise these
individuals with known autosomal dominant or other well
characterised single-gene mutations.
Cohorts of patients with preclinical AD are likely to
attract growing interest for intervention trials to prevent
AD.70 It is possible that in the future, disease-modifying
treatments could be directed at clinically asymptomatic
individuals with biological evidence of Alzheimer’s
pathology who are at highest risk of further developing
clinical AD.71 The presymptomatic population is attractive
given the certainty of AD, but this group is very rare (0·3%
of AD cases). Asymptomatic individuals “at risk for AD”
are more common, but this population has a lower risk of
developing AD. However, the probability of subsequent
development of clinical AD can be substantially increased
by recruiting asymptomatic individuals with a combination
of risk factors (eg, older age, APOE ε4 genotype, increased
retention of amyloid radioligand in the brain, and evidence
of age-related decreased volume of the hippocampus),36,40–43
but without achieving certainty that AD will develop or by
when. Because of this uncertainty and for ethical reasons,
we emphasise that reference to preclinical AD should be
avoided. Accordingly, at the diagnostic or clinical level, any
(clinically asymptomatic) individual should be described
as being “at risk for AD” or having “asymptomatic
amyloidopathy”, but should not be defi ned as having
preclinical AD (panel, table 2).
Prodromal (predementia) Alzheimer’s disease
The term “prodromal AD” was introduced recently.72,73 It
characterises clinically aff ected patients who do not yet
have dementia (predementia) and who are diagnosed to
have AD on the basis of their clinical presentation and
(Continued from previous page)
Preclinical states of AD (including both “asymptomatic at-risk state for AD” and
These terms refer to the long asymptomatic stage between the earliest pathogenic events/
brain lesions of AD and the fi rst appearance of specifi c cognitive changes. Traditionally, a
preclinical or asymptomatic phase was recognised post mortem by evidence of histological
changes typical of Alzheimer’s pathology in individuals considered as cognitively normal
before death. Today, two preclinical states can be isolated in vivo:
• Asymptomatic at-risk state for AD—this state can be identifi ed in vivo by evidence of
amyloidosis in the brain (with retention of specifi c PET amyloid tracers) or in the CSF
(with changes in amyloid β, tau, and phospho-tau concentrations). In the absence of
knowledge about the value of these biological changes to predict the further
development of the disease, the asymptomatic phase of AD should still be referred to
as an “at-risk state for AD”.
• Presymptomatic AD—this state applies to individuals who will develop AD. This can be
ascertained only in families that are aff ected by rare autosomal dominant monogenic
AD mutations (monogenic AD).
This term refers to the underlying neurobiological changes responsible for AD that
span the earliest pathogenic events in the brain and that include specifi c neuronal brain
lesions (senile neuritic plaques and neurofi brillary tangles), synaptic loss, and vascular
amyloid deposits within the cerebral cortex. This term can be applied irrespective of the
existence of clinical manifestation.
Mild cognitive impairment (MCI)
This term applies to individuals with measurable MCI in the absence of a signifi cant eff ect
on instrumental activities of daily living. This diagnostic label is applied if there is no disease
to which MCI can be attributed. It remains a term of exclusion for individuals who are
suspected to have but do not meet the proposed new research criteria for AD, in that they
deviate from the clinicobiological phenotype of prodromal AD because they have memory
symptoms that are not characteristic of AD or because they are biomarker negative.
www.thelancet.com/neurology Vol 9 November 2010 1123
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
defi nition of AD proposed in this lexicon encompasses
prodromal AD. Previously, individuals with the features
of prodromal AD were described as having MCI,74 with an
increased risk of developing AD, but not as having
identifi able AD. The proposed conceptual shift is to
consider a patient previously diagnosed as having MCI
(ie, with an amnestic syndrome of the hippocampal type
and with biomarker evidence positive for brain
amyloidosis) to be no longer at risk for developing AD
dementia, but to recognise that they already have AD at a
prodomal stage with an inevitable progression to AD
dementia over time. A clinical phenotype combined with
biomarker evidence will now no longer be predictive of
AD but diagnostic, in accordance with the new criteria.
The diagnosis of prodromal AD is preferred to that of
MCI, because identifying the disease responsible for the
syndrome is more valuable for the patient in terms of
prognosis and treatment. The term “prodromal AD” is
proposed in reference to the dementia phase (panel). It
might subsequently disappear if AD is considered
universally to encompass both the predementia and
dementia stages (panel).
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, fi nancial capacity, and those related to caregiving.
Given this transitional signifi cance, the time to
Alzheimer’s dementia from its prodromal stage might be
a useful outcome measure to consider for the study of
effi cacy of disease-modifying treatments,71 although the
precise time of progression to this threshold might
remain diffi cult to establish.31,76 The dementia threshold
separates clinical AD into two diff erent symptomatic
phases: the prodromal (predementia) phase and the
dementia phase (panel).
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 neurofi brillary 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 which an
amnestic syndrome of the hippocampal type occurs as an
early core manifestation,56 often associated with less
specifi c changes in executive functions, naming abilities,
or attention resources. Accordingly, the new research
criteria emphasised the presentation of a signifi cant
progressively worsening episodic memory defi cit that
remains predominant in the course of the disease (panel).
They focused on this phenotype because it is the most
frequent,1 and it has been associated with post-mortem
Alzheimer’s pathology in all examined cases.79
An amnestic syndrome of the hippocampal type is now
a core feature that is essential for the diagnosis of typical
AD.56 This syndrome is established on the basis of
patient/informant reports of memory decline and of
objective evidence of episodic memory impairment on
tests that control for an eff ective registration of the items
to be remembered and probe response to cueing as a
measure of the storage abilities and associative function
of the hippocampus. The amnestic core diagnostic
criterion is also required in more advanced cases, in
which the history of an early and signifi cant episodic
memory defi cit increases the specifi city of the diagnosis
of clinical AD. Patients with typical AD are of interest for
pharmaceutical trials because high diagnostic specifi city
AD diagnosis Presence of impairment on
specifi ed memory tests
biomarkers in vivo
Specifi c clinical presentation
Absence of dementia
Presence of dementia
Asymptomatic at risk for AD
Yes RequiredRequired Evidence of comorbid disorders
Absence of symptoms of AD
Absence of symptoms of AD and presence of
monogenic AD mutation
Absence of symptoms or biomarkers specifi c for ADMild cognitive impairment NoNot required Not required
Table 2: Comparative features of the diff erent conditions described in the new lexicon according to the new research criteria framework6
www.thelancet.com/neurology Vol 9 November 2010
is required for the development of drugs directly targeted
against the pathogenic mechanisms of AD (panel).
Atypical Alzheimer’s disease
There are well defi ned 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-
fl uent aphasia, logopenic aphasia, posterior cortical
atrophy,9 and frontal variant AD.80,81 With the advent of
biomarkers providing in-vivo confi rmation of Alzheimer’s
pathology, it is now possible to include these clinical
disorders as atypical AD if there is such biomarker
support.55,79 These disorders might present with an
amnestic defi cit only later in the disease course.
Until recently, the AD aetiology of these disorders was
under-recognised clinically and only identifi ed at post
mortem if there was a compatible pattern of histological
changes.18,82 We propose to use the diagnostic label of
atypical AD for well characterised clinical presentations
(primary progressive aphasia, logopenic aphasia, posterior
cortical atrophy, frontal variant) only if they are supported
by a positive pathophysiological biomarker study of
Alzheimer’s pathology, because these clinical conditions
could also result from other pathological processes. The
term “atypical” in these cases is applied only because the
specifi c clinical presentations are much less common
than the amnestic presentation. We anticipate that these
atypical clinical syndromes will become better recognised
and in turn more frequent in the future with the availability
of in-vivo biomarkers of Alzheimer’s pathology.
Pathophysiological markers including low amyloid β
and high tau CSF concentrations and increased retention
of PET amyloid tracers are anticipated to have the same
use as in the diagnosis of typical AD, although this
remains to be validated. Topographical markers need to
be considered with regard to the specifi c regional
anatomical distribution of pathology that characterises
each syndrome. Neuroimaging markers have been found
to closely refl ect both the clinical syndrome and the
underlying distribution of pathology.83,84 Neuroimaging
markers that are uniquely associated with each described
variant are likely to be refi ned. In consideration of
important genetic factors, the presence of a proven
autosomal dominant mutation within the immediate
family is taken as suffi cient evidence to support a
diagnosis of atypical AD when clinical features fall
outside the typical criteria (panel).
Mixed Alzheimer’s disease
Mixed AD is a diagnostic confound representing the
co-occurrence of Alzheimer’s pathology with other
biological causes of cognitive
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 Clinical diagnostic consideration for mixed AD
could be supported in the setting of an otherwise typical
clinical phenotype of AD by one of several elements,
including past or recent history of stroke, presence of gait
disturbances, parkinsonism, hallucinations/delusions,
cognitive fl uctuations, and evidence of signifi cant levels of
small vessel ischaemic changes, strategic lacunar infarcts,
or large vessel infarcts on brain imaging. However,
detecting these co-occurrences in a patient with multiple
disorders that potentially aff ect cognitive performance
does not equate to proof of multiple causation. Although
mixed dementia has never been properly operationalised,
we propose that history of stroke in the absence of imaging
signs of cerebrovascular disease or imaging signs of
cerebrovascular disease in the absence of clinical
symptoms of stroke are not suffi cient to support a
diagnosis of mixed dementia due to Alzheimer’s pathology
and cerebrovascular disease. Accordingly, to avoid an
unsupported infl ation of mixed dementia cases, we
recommend reserving the “mixed AD” label for cases for
which both clinical features and diagnostic markers point
to a mixed aetiology. For example, a typical AD phenotype
with white matter changes cannot be diagnosed as mixed
AD in the absence of motor symptoms or gait disturbances
consistent with the distribution of vascular pathology.
The advances in biomarker development now allow
biological evidence to be used in support of a diagnosis
of mixed AD. This might improve the classifi cation of
AD patients with comorbid disorders. The caveat is that
cerebrovascular disease can result in increased
concentrations of CSF total tau, so this biomarker should
not be used to support such a diagnosis, whereas low
CSF amyloid β or positive amyloid-ligand PET imaging
are suffi cient to establish such a diagnosis. In the case of
AD with Lewy bodies, the situation is even more complex
because low CSF amyloid β and increased amyloid-ligand
binding have been reported.85–88 In this setting, there is a
limited ability to reliably identify Lewy bodies with in-
vivo biomarkers. The most accurate approach to the Lewy
body portion of the diagnosis is through phenotypic
identifi cation that includes the presence of extrapyramidal
signs, hallucinations, and cognitive fl uctuations,89 with
positive dopamine transporter imaging that provides
evidence of presynaptic dopaminergic denervation in the
striatum,90,91 consistent with the diagnosis of dementia
with Lewy bodies.89,92
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 reclassifi ed
by their aetiology, they are no longer included within an
MCI grouping. In the absence of any specifi cations of the
www.thelancet.com/neurology Vol 9 November 2010 1125
memory profi le and of any reference to specifi c biomarkers,
MCI or amnestic MCI remains a syndromic classifi cation
that cannot be used for the diagnosis of prodromal AD.
Because it is possible to diagnose AD at the prodromal
stage, MCI now includes individuals who do not meet
criteria for prodromal AD. This term is also valuable for
those without a clear diagnosable disease. Accordingly, it
remains a useful clinical designation for describing
individuals who have a memory defi cit characteristic of
prodromal AD (ie, amnestic syndrome of hippocampal
type), but when biomarker evidence of Alzheimer’s
pathology is absent, uncertain, or testing has not been
done. MCI would also apply to individuals with mild
cognitive impairment or memory disorders that are not
consistent with prodromal AD, although biomarker
evidence is present (panel).
The value of these defi nitions is their potential
application in clinical trials of disease-modifying drugs.
Individuals identifi ed 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 defi nitions will assist in
constructing trial populations and comparing results
across trials. We acknowledge that there are diff erent
opinions on the terminology and that this lexicon is a
proposal that will require revisions and updating by the
scientifi c community.
BD, HHF, CJ, and PS developed the concept of the new lexicon. BD and
HHF wrote the paper, which was critically revised by all authors, who
individually approved the fi nal version. BD had full access to all
discussions and had fi nal responsibility for the decision to submit the
paper for publication.
Confl icts of interest
BD has consulted or served on advisory boards for Bristol-Myers Squibb,
Novartis, Roche, Elan, Eli Lilly, Eisai, GE Healthcare, Janssen, and
Sanofi -Aventis. His institution has received grants from Novartis, Roche,
Eisai, and Sanofi -Aventis. HHF has consulted or served on advisory
boards and/or study steering committees for AstraZeneca, Bristol-Myers
Squibb, Elan, Janssen, Merck Serono, Lundbeck, Novartis,
Neuropharma, Wyeth, Noscira, Servier, Glia Scientifi c, Eisai, and Pfi zer.
He has received grants for clinical trials sponsored by Elan
Pharmaceuticals and Sanofi Synthelabo and performed at the University
of British Columbia (UBC). He has received travel/accommodation
covered or reimbursed for CME programmes from the Academy of
Health Care Education, Alpha Plus, Cadmus Media, Janssen Pharma,
Lundbeck, Eisai, AstraZeneca, Pfi zer, Medical Decision Point, Informed
Direct PLC, Med Plan Communications, and Novartis. He has held
stock in Biomarin. From Jan 1, 2009, he has been on leave from UBC
and is a full-time employee of Bristol-Myers Squibb. JLC has provided
consultation to Abbott, Acadia, Accera, ADAMAS, Astellas, Avanir,
Bristol-Myers Squibb, CoMentis, Eisai, Elan, EnVivo, Forest,
GlaxoSmithKline, Janssen, Lilly, Lundbeck, Medivation, Merck, Merz,
Myriad, Neuren, Neurokos, Novartis, Noven, Orion, Pfi zer, Prana,
reMYND, Schering Plough, Signum Bioscience, Sonexa, Takeda,
Toyama, and Wyeth pharmaceutical companies, and to Bayer,
MedAvante, Neurotrax, and UCB. He holds stock in ADAMAS, Prana,
Sonexa, MedAvante, Neurotrax, and Neurokos. He has been a speaker/
lecturer for Eisai, Forest, Janssen, Novartis, Pfi zer, Lundbeck, and Merz,
owns the copyright of the Neuropsychiatric Inventory, and has provided
expert witness consultation regarding olanzapine and ropinerol. STDK
has collaborated with the American Board of Psychiatry and Neurology,
Bristol-Myers Squibb, and the University of Virginia School of Medicine.
PB-G has no personal confl icts of interest; her institution has received
grants from Novartis, Beaufour Ipsen Pharma, Scor Global Life,
Danone, and Lesieur. GF has no personal confl icts of interest; his
institution has received a grant from the Alzheimer’s Association. NCF
has served on advisory boards for the Alzheimer’s Research Forum and
GE Healthcare. His institution has received remuneration, honoraria,
and trial support from Abbott, the American Neurological Association,
Lundbeck, GE Healthcare, GlaxoSmithKline, Elan Pharmaceuticals, Eli
Lilly, Lundbeck, Eisai, IXICO, Pfi zer, Janssen, the Movement Disorders
Society, Wyeth Pharmaceuticals, Sanofi -Aventis, and Coalition Against
Major Diseases Consortium as a result of his consultancy and advisory
work. DG has served on the data safety monitoring board for a clinical
trial for Jansen Pharmaceutical. GAJ has collaborated with Medivation,
Martek Biosciences, and Avanir. JO’B has received honoraria for non-
promotional talks and travel/accommodation expenses from Pfi zer,
Eisai, Shire, Novartis, and Lundbeck, and his institute has undertaken
consultancy work for GE Healthcare and Bayer Healthcare. FP has
collaborated with Bayer Healthcare; her institution has received grants
and honoraria from Servier, Bioprojet, Lundbeck, Eisai, Wyeth,
Medivation, Exonhit Therapeutics, and Bristol-Myers Squibb. PR has
collaborated with Lundbeck, Merck, Novartis, Janssen-Cilag, and Eisai.
MR has served on a safety monitoring committee for Elan
Pharmaceuticals, and is Director of the UK Dementia and
Neurodegenerative Diseases Clinical Research Network. MS has
collaborated with Eisai, Pfi zer, Lundbeck, and Servier. LCdS has
collaborated with Lundbeck. YS has collaborated with or consulted for
Allergan, Cephalon, Elan, Eisai, Pfi zer, Ortho-McNeil Neurologics,
Merck & Co, GlaxoSmithKline, Eli Lilly, and Janssen-Cilag. PJV has
served on advisory boards for Bristol-Myers Squibb, Myriad, Elan-
Wyeth, and Ipsen, and has consulted for Danone. His institution has
received grants and honoraria from Bristol-Myers Squibb, Diagenic,
Novartis, and Lundbeck. PS reports no personal confl ict of interest; his
institution has received grants from Wyeth, Elan, Genentech, Danone,
Novartis, and Janssen-Cilag. CJ has participated in a scientifi c advisory
board meeting organised by Bristol-Myers Squibb. AD, SG, HH, KM,
and SS report no confl icts of interest. BD, HHF, NCF, and STDK have
been involved in the working group of the American Association for the
Revision of the NINCDS–ADRDA criteria for Alzheimer’s disease.
The International Working Group received fi nancial funding from Eisai
France to support the meeting room cost for the ICAD 2009 meeting.
The authors gratefully acknowledge discussion with Lon Schneider,
University of Southern California, concerning the manuscript.
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