Comparison of International Working Group criteria and National
Institute on Aging–Alzheimer’s Association criteria for
Pieter Jelle Vissera,b,*, Stephanie Vosa, Ineke van Rossumb, Philip Scheltensb
aDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht,
bAlzheimer Center/Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands
Abstract Two sets of research criteria for Alzheimer’s disease are now available: those published by an
International Working Group in 2007, and the recommendations published by the National Institute
on Aging and the Alzheimer’s Association (NIA–AA) in 2011. They both provide guidelines for the
diagnosis of asymptomatic and symptomatic Alzheimer’s disease. The coexistence of two sets of cri-
teria for the same disorder raises the question of which set of criteria should be preferred. A compar-
ison of the criteria revealed differences in approach, terminology, and use of cognitive markers and
AA criteria and vice versa. However, the NIA–AA criteria allow for a subclassification of persons
based on biomarker results within each diagnostic category. Further research is needed to validate
the criteria. Modifications are likely to be made before the criteria can be used in daily practice.
? 2012 The Alzheimer’s Association. All rights reserved.
Keywords:Alzheimer’s disease; Diagnosis; Biomarkers; Neuropsychology; MCI
Two sets of research criteria for Alzheimer’s disease
(AD) are now available: those published by an International
Working Group (IWG) in 2007, and those published by the
National Institute on Aging and the Alzheimer’sAssociation
(NIA–AA) in this Journal in 2011 [1–4]. The coexistence of
two sets of criteria for the same disorder raises the question
of which set of criteria should be used. In this commentary,
we will compare the two sets of criteria, highlight their
strengths and limitations, and discuss future perspectives.
2. Approach and terminology
ofADbiomarkersand cognitive impairments:a prepathology
stage (biomarkers normal, no cognitive impairments), an
asymptomatic stage (biomarkers abnormal, no cognitive im-
pairments), and a symptomatic stage (biomarkers abnormal,
subdivided into a subjective cognitive impairment stage
(AD-SCI), a mild cognitive impairment stage (AD-MCI),
and a dementia stage (AD-dementia). Both the IWG criteria
and NIA–AA recommendations deal with the asymptomatic
and symptomatic stages of AD but the approaches and termi-
nology differ (Figure 1).
2.1. IWG criteria
The IWG proposes two sets of criteria. Both sets of crite-
ria require assessment of AD biomarkers. The first set of cri-
to as “preclinical AD.” In the 2010 revision, “preclinical
AD” was subdivided into “asymptomatic at risk for AD”
and “presymptomatic AD” . This latter category applies
to asymptomatic subjects who are carriers of autosomal
jects with symptomatic AD and is referred to as “AD.” Sub-
jects who meet these criteria can be subclassified as
*Corresponding author. Tel.: 31 (0)43 388 1041; Fax: 31 (0)842 134
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1552-5260/$ - see front matter ? 2012 The Alzheimer’s Association. All rights reserved.
Alzheimer’s & Dementia 8 (2012) 560–563
“prodromal AD” or “predementia AD” (the AD-MCI stage
in Figure 1) or “AD dementia” (the AD-dementia stage in
Figure 1). Persons with AD-SCI cannot yet be classified
by these criteria. The authors indicate that further research
is needed before it can be decided whether subjects with
AD-SCI should be considered as having AD or as being
asymptomatic at risk for AD .
2.2. NIA–AA recommendations
The NIA–AA proposes three sets of criteria in cases
where biomarkers are available: one for the asymptomatic
stage, called “preclinical AD,” one for the AD-MCI stage,
called “dementia due to AD.” In cases where no biomarkers
can be used for the diagnosis, subjects should be classified
according to clinical criteria. Persons with dementia can
be diagnosed as probable or possible AD and persons with
MCI as MCI.
3. Cognitive criteria
The main difference between the cognitive criteria in the
two sets is in how they deal with nonmemory impairments.
3.1. IWG criteria
The AD criteria require impairment on an episodic mem-
ory test that preferably has encoding specificity. Dementia is
not necessary, although a subdivision into prodromal AD
and AD dementia can be made, as described previously. In
the 2010 update, it was shown that persons with nonmemory
impairments can meet the AD criteria as well, but only if
they have a well-defined syndrome such as primary progres-
sive nonfluent aphasia, logopenic aphasia, frontal variant of
AD,orposterior cortical atrophy.These subjects are referred
to as atypical AD .
3.2. NIA–AA recommendations
In the NIA–AA criteria, memory impairment is not nec-
essary for the diagnosis. The criteria for MCI due to AD
require MCI, either amnestic or nonamnestic. These MCI
criteria are similar to those published in 2004 [6,7]. The
criteria for dementia due to AD require impairments in
multiple cognitive domains and interference in activities of
daily living. For the diagnosis of dementia, memory
impairment is not necessary either.
4. Biomarker criteria
Both sets of criteria rely essentially on the same bio-
markers for AD pathology, that is, b-amyloid (1-42) in cere-
brospinal fluid (CSF); amyloid deposits, as measured by
positron emission tomographic (PET) scanning; tau in CSF;
hippocampal atrophy, as measured by magnetic resonance
imaging (MRI); or hypoperfusion or hypometabolism, as
measured by PET or single-photon emission computed
tomography imaging. They differ in how they combine these
biomarkers for the diagnosis.
4.1. IWG criteria
In the original criteria, biomarkers were subdivided
according to modality (CSF, PET, or MRI). In the 2010 revi-
sion, biomarkers were classified as pathophysiological
markers (markers for amyloid or tau) and topographical
markers (other biomarkers) . An abnormal score for any
AD biomarker (pathophysiological or topographical) is suf-
ficient to fulfill the biomarker criterion for AD [1,5]. In
subjects with preclinical AD, pathophysiological markers
should be abnormal .
4.2. NIA–AA recommendations
The NIA–AA criteria make a distinction between amy-
loid markers and neuronal injury markers (other bio-
Persons with preclinical AD are classified into three
stages based on biomarkers and cognitive markers
(Table 1). Persons with abnormal amyloid markers only
are in stage 1, subjects with both abnormal amyloid and
injury markers are in stage 2, and persons with both
DAl a c i n i l c e r P
my sADAr o fk s i r t a c i t amo t p
a i t nemedDADA l amo r do r P
DAo teud a i t nemeDDAo teudICM
ega t sICS -DA
ega t sa i t nemed -DA
ega t sICM-DA
DA c i t amo t pmyS
s ega t sDA
DAl a c i n i l c e r P
s eg a t S
3ega t S
2 - 1
DAyg o l o h t ap e r P
DA c i t am o t pm y sA
Fig. 1. Terminology of AD stages. Abbreviations: AD, Alzheimer’s disease; SCI, subjective cognitive impairment; MCI, mild cognitive impairment; IWG,
International Working Group; NIA–AA, National Institute on Aging–Alzheimer’s Association.
P.J. Visser et al / Alzheimer’ s & Dementia 8 (2012) 560–563561
abnormal amyloid and injury markers and subtle cognitive
impairments, including SCI, are in stage 3.
Persons with MCI or dementia due to AD are classified
based on amyloid and neuronal injury markers (Table 2).
If both amyloid and neuronal injury markers are abnormal,
thelikelihood for ADishigh. Ifonlyamyloidorneuronal in-
jury markers have been measured and the test is abnormal,
the likelihood is intermediate. If the amyloid marker is ab-
normaland theneuronalinjury marker normal,orviceversa,
the biomarkers are considered uninformative.
5.1. Strengths and limitations
A strength of the IWG criteria for AD is that that they
cover the clinical spectrum from MCI to dementia. This cir-
cumvents the arbitrary, and sometimes difficult, distinction
between MCI and dementia. Limitations are the strong em-
phasis on memory impairment, as nondemented subjects
with AD may present with nonmemory impairments [8,9].
Moreover, the term “prodromal AD” for subjects with AD-
MCI may be confusing. The authors use this term to indicate
that these subjects are prodromal to the dementia stage.
However, “prodromal” could be easily understood as pro-
dromal to AD itself, although these subjects meet the IWG
tion between amyloid and injury markers in the criteria for
symptomatic AD. Also, the broad definition of cognitive im-
that the diagnoses change with disease progression, which
may cause confusion to clinicians and patients. Another lim-
itation is that the ranking of biomarkers in persons with MCI
results. Unpublished data from our own cohorts showed that
60% of the subjects with MCI had conflicting scores for
CSF b-amyloid (1-42), CSF tau, and hippocampal atrophy.
A limitation of both sets of criteria is that in persons with
the same diagnostic accuracy for AD. The amyloid cascade
hypothesis, however, states that amyloid pathology marks
the start of AD and that neuronal injury is a secondary event
. Amyloid markers will, therefore, have a higher sensi-
tivity for AD than injury markers, whereas injury markers
will have a higher specificity .
5.2. Classification of subjects according to the criteria
NIA–AA criteria and vice versa. Subjects with nonamnestic
MCI who meet the NIA–AA MCI due to AD criteria but not
the IWG criteria may form the only exception. An important
a person with MCI who meets the IWG criteria will meet the
classifiedtohave ahigh orintermediate likelihood for AD or
to have uninformative biomarker results.
5.3. Use of the criteria
The current use of the criteria will be for research, as em-
phasized by both the IWG and the NIA–AAworking group.
Which set of criteria should be preferred will depend on the
IWG and NIA–AA criteria for AD-MCI and AD-dementia
Any amyloid or injury marker High likelihood
Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive impairment.
NOTE. 1 5 abnormal; 2 5 normal; ? 5 not tested.
IWG and NIA–AA criteria for asymptomatic AD
Stage 1 Stage 2 Stage 3
Amyloid or tau abnormal
Amyloid and injury marker abnormal
Subtle cognitive decline
Amyloid and injury marker abnormal
Abbreviations: IWG, International Working Group; NIA–AA, National Institute on Aging–Alzheimer’s Association.
P.J. Visser et al / Alzheimer’ s & Dementia 8 (2012) 560–563562
purposeofthestudy.Forexample,recentAD-MCItrialswith Download full-text
amyloid-modifying treatments selected subjects with amy-
loid markers [12,13]. These persons would meet the IWG
AD criteria or the NIA–AA MCI due to AD criteria with
intermediate likelihood for AD. In case a study requires
including subjects with an increased risk for cognitive
decline, a combination of amyloid and injury markers
could be used, such as the NIA–AA MCI or dementia due
to AD criteria with a high likelihood for AD [14–18].
5.4. Future perspectives
from AD biomarker studies into guidelines for diagnosis.
Further research is needed to validate the criteria. It seems
useful toreconsider the ranking of biomarkers in the criteria,
such that amyloid markers are used for the diagnosis and in-
jury markers for the staging of the disease and for prognosis
[14–18]. In the meantime, clinicians can apply biomarkers
diagnostic criteria. In persons with dementia, biomarkers
may, for example, help to differentiate between AD and
frontotemporal lobar dementia . In persons with MCI,
AD biomarkers may be tested if the patient asks to know
tients should not be tested for AD biomarkers with the only
goal being to classify them according to the new criteria.
The study was in part funded by the European Commun-
ity’s Seventh Framework Programme (FP7/2007-2013) un-
der grant agreement no. 211696 (P.J.V. and I.v.R.), and the
Centre for Translational Molecular Medicine (www.ctmm.
nl), project LeARN, grant 02N-01 (P.J.V. and S.V.).
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