Alzheimers & Dementia 7 (2011) 253256
Editorial
Revised criteria for diagnosis of Alzheimers disease: National Institute
on Aging-Alzheimers Association diagnostic guidelines
for Alzheimers disease
The publication of revised criteria/guidelines for the diagno-
sis of Alzheimers disease (Dx-AD) in the current issue of
Alzheimers & Dementia is a momentous milestone in the
prolonged history of efforts to characterize the distinct
clinical-pathological features of a complex syndromeAlz-
heimers disease (AD). The amendments to the current
criteria recommended by the National Institute on Aging
(NIA)-Alzheimers Association workgroups on diagnostic
guidelines for Alzheimers disease represent significant prog-
ress in that endeavor by adding important new features that
would enhance the precision and accuracy of differential diag-
nosis of this syndrome. These revisions promise to have a pro-
found impact on the pace and direction of future research as
well as the global effort to find a cure. Our field owes a great
debt of gratitude to the members of the three workgroups, as
well as to the NIA and the Alzheimers Association, for their
leadership in crafting the first significant revision of the
NINCDS-ADRDA (National Institute of Neurological and
Communicative Disorders and Stroke and the Alzheimers Dis-
ease and Related Disorders Association) criteria [1] of 1984.
Much of what the NIA-Alzheimers Association work-
groups are recommending is a redefinition of AD to include
3 stages: 1) a dementia stage for which the original
NINCDS/ADRDA and the revised National Institute on
Aging/Alzheimers Association criteria apply; 2) a mild cog-
nitive impairment (MCI) stage where there are core criteria
for MCI but only guidelines of how to relate MCI to AD after
further research and validation of biomarkers; and 3) a preclin-
ical stage where there are no criteria for diagnosis but, instead,
presentation of a staging hypothesis for further research re-
lated to the use of biomarkers to identify people with changes
in the brain consistent with those seen later in MCI and AD
dementia. An important point for all three stages is that the
workgroups have created a framework for research on the re-
lationship of the underlying pathophysiology to the emergence
of clinical symptoms. In addition, for MCI and AD dementia,
basic diagnostic criteria for use in current clinical practice are
presented.
The purpose of this editorial is to provide a brief historic
context to the significance of the proposed revisions to the
1552-5260/$ - see front matter 2011 The Alzheimers Association. All rights reserved.
doi:10.1016/j.jalz.2011.04.003
Dx-AD criteria and offer recommendations for further
action in the future concerning this work-in-progress.
One of the questions concerning this revision iswhy there
was a 27 years hiatus between the publication of the original
criteria and current version? Perhaps the next reiterations of
these criteria will occur at regular and shorter intervals. The
issue of a long lag time between re-evaluation/revision of
Dx-AD criteria is a serious matter for future progress in the
field; however, this concern needs to be moderated in the con-
text of early struggles to advance the field. Although the study
of dementia has a 100-year history, systematic efforts to ad-
dress the array of scientific and clinical challenges to differen-
tial diagnosis of AD syndrome is a relatively recent
phenomenon. Thus, several hurdles had to be overcome before
the 1984 NINCDS-ADRDA criteria as well as during the inter-
vening period between 1984 and 2011 (e.g., the lack of vali-
dated assessment tools, the necessary infrastructure for
systematic clinical/longitudinal studies).
Historically, one of the early core issues for the field of
dementia was the question of whether AD changes are sim-
ply an accentuation of normal senescence. Even today, this
problem remains to be a critical challenge. The landmark in-
vestigations by Blessed et al [2] began to address this issue in
late 1960s and set the stage for the subsequent efforts to dis-
tinguish brain changes owing to pathology from those asso-
ciated with healthy aging.
In the United States, the trend for integrating clinical and
biological studies of dementia (i.e., clinico-pathological cor-
relations) started to take shape a decade later in parallel with
advances in neurochemistry, histology, electron microscopy,
neuroanatomy, molecular biology, genetics, and imaging.
The critical event that set the stage for this approach was
the 1977 seminal workshop (published in 1978) organized
by the NINCDS, NIA, and National Institute of Mental
Health, chaired by Robert Katzman, Robert Terry, and
Katherine Bick [3].
Subsequently, in 1978, the NIA began to build its extramu-
ral program on AD by focusing on developing the infrastruc-
ture and tools for such clinical-pathological studies. The
institute placed high priority on developing, standardizing,
254 Z.S. Khachaturian / Alzheimers & Dementia 7 (2011) 253256
and validating various assessment instruments, diagnostic
procedures, as well as fostering the formulation of distinct di-
agnostic criteria for clinical workup and neuropathological
evaluation [46]. These early efforts by NIA led to the
creation of an array of quantitative measures of cognition.
Other program initiatives, which promoted the validation of
instruments for objective evaluation of symptoms, were
critical preliminary steps in developing the capabilities of
the field for systematic characterization of the AD
syndrome. These early efforts to encourage the
development and validation of the necessary tools and
infrastructure for assessment of the disease took time, but
also became the foundation for much of the current routine
clinical-workup, and set the standard for clinical staging
methods as an essential element of clinical criteria.
One of the other critical barriers for systematic clinico-
pathological studies was the lack of widely agreed upon cri-
teria for the neuropathological evaluation of putative cases of
people with AD syndrome, as compared with healthy aging
brains. This problem was addressed by a Research Planning
Workshop on Diagnosis of Alzheimers Disease, organized
by NIA in 1983 (published in 1985 [4]).The recommenda-
tions of this workshop led to several program initiatives
that prepared the ground for the next 27 years of research
on clinico-pathological correlations, as well as some of the
issues covered by the current NIA-Alzheimers Association
Dx criteria presented in this issue. For example, the Neuropa-
thology Panel of NIAs 1983 workshop on AD-Dx took the
first step toward defining the minimum microscopic criteria
necessary for histological diagnosis of AD. The Neurology
Panel suggested that the term Alzheimer Disease be
reserved for patients who show a compatible clinical course
along with the histopathological and neurochemical changes
associated with the disease. The panel also considered the
problem of distinguishing AD from benign senescent forget-
fulness (mild cognitive impairment) and non-AD-type
dementia. Other topics and recommendations of this work-
shop included neuroimaging, biomarkers, molecular genet-
ics, longitudinal studies, brain banks, establishment of
family registries and pedigree studies, animal models, and
the need for research on normal brain aging.
Before 1984, in the absence of specific diagnostic criteria
for AD, the Diagnostic and Statistical Manual of Mental Dis-
orders (DSM-III/IV) criteria [7] for diagnosis of dementia
had fulfilled the requirements of clinical research. Finally,
this need was addressed with the dual publications of: (a)
NINCDS-ADRDA Diagnostic Criteria [1] and (b) NIAs
Diagnosis of Alzheimers Disease [4]; these two corollary
criteria specified not only inclusion/exclusion factors with
three levels of confidence (McKhann criteria [1]) but
also an objective quantitative measure for histopathological
confirmations (Khachaturian criteria [4]with its subse-
quent revisions [8,9]).
After the challenges of developing criteria and objective
assessment instruments were overcome, the next major im-
pediment for advancing knowledge on the clinical-
pathological relationships was the need for infrastructure
to promote/facilitate multisite collaborative studies on:
 Validation the diagnostic criteria with neuropathologi-
cal evaluation/other biomarkers.
 Standardization (including measures ofreliability,
sensitivity, specificity) various clinical assessment in-
struments.
 Construction of new measurements for tracking
changes in behaviors and symptoms of various do-
mains of cognition.
Several of the programs and initiatives launched by NIA
during the period of 1978 to 2011 (e.g., Centers Program,
Consortium to Establish a Registry for Alzheimers Disease
[CERAD], Alzheimers Disease Clinical Studies [ADCS],
Alzheimers Disease Neuroimaging Initiative [ADNI])
were designed, in part, to enable the development and valida-
tion of quantitative objective assessment technologies and al-
gorithms for earlier and earlier detection of the AD syndrome.
For example, the Alzheimers Disease Patient Registry Pro-
gram was launched in 1986 to address the goal of developing
standardized diagnostic assessments. This program included
the CERAD led by Al Heyman and Gerda Fillenbarum, the
Mayo Clinic Registry led by Len Kurland and Ron Peterson,
the Seattle site led by Eric Larson, the Mon valley project with
Lewis Kuller and Mary Ganguli, and Denis Evanss group in
East Boston. The CERAD project was successful in establish-
ing uniform methods for the diagnosis and assessment of AD
because of the dedicated and effective leadership provided by
Al Heyman and the cooperation of clinicians and investiga-
tors nationwide and worldwide. Overall, the Alzheimers
Disease Patient Registry program was instrumental not
only in the development of assessment instruments/proce-
dures for standardization but also in helping to refine the con-
cept mild cognitive impairment.
During the last 27 years, the improvements in the accuracy
of the clinical diagnosis have been remarkable. The proce-
dures for clinical assessment and differential Dx-AD steadily
advanced toward well-validated algorithms for identification
of positive clinical phenotypes of the diseases. Early diagno-
sis has become one of the most important clinical accom-
plishments with profound implications for: (1) research, (2)
establishing the prevalence of AD, (3) initiating treatment
when it may have optimal benefit, and (4) understanding
the pathobiology of the disease. There is a general consensus
that many of the advances in diagnosis, treatment(s), care,
and understanding the cause(s) would not have been possible
without the creation of instruments, criteria, infrastructure,
and programs that support interdisciplinary research. Some
of the spectacular clinical and research strides are attribut-
able in large measure to the NIA initiatives since 1978.
Thus, the publication of these newly revised criteria by the
NIAAlzheimers Association workgroups on diagnostic
guidelines for Alzheimers disease has not only written the
coda for a prolonged history of scientific efforts to character-
ize the clinical features of dementia but it has also brought the
 Z.S. Khachaturian / Alzheimers & Dementia 7 (2011) 253256
field to the threshold of a new frontierthe struggle toward
primary prevention [10]. The new challenges for the field
are no less ambitious or difficult to overcome as compared
with those that were confronted three decades ago when de-
mentia was an obscure neurological condition confused with
senility. However, the field cannot wait for another three de-
cades for a re-evaluation of the protocols for characterizing
the AD syndrome in its various stages of progression.
The following are some suggestions for consideration by
the NIAAlzheimers Association workgroups on diagnostic
guidelines for Alzheimers disease:
 The workgroups should be chartered by NIA and Alz-
heimers Association to remain active for an indefinite
period and commissioned to publish revisions at regular
intervals (34 years) and/or when substantial numbers
of subjects (e.g., 5000) have been evaluated with the
new criteria. Thus, the current amendments to the crite-
ria should be considered as work-in-progress; repre-
senting only the beginning of a new process for regular
re-evaluation/ revisions rather than an end in itself.
 The workgroups should adopt a formal nomenclature
for these criteria and its revisions (e.g., similar to
DSM).
 The membership of the workgroups should be ex-
panded to reflect international perspective and related
ancillary disciplines.
 The NIA-Alzheimers Association should develop
a multisite collaborative program or initiative for
formal evaluation/validation of the new criteria in
a proactive manner either through existing programs
(e.g., ADC, ADCS, ADNI) or the launch of a new pro-
gram.
 As a prelude to the next reiteration to the criteria, the
field needs to re-evaluate the current conceptual model
of the disease/syndrome and consider alternative
models. The most compelling reason for a new model
of pathogenesis is the need to address the issue of
mixed pathologies, which increasingly appear to be
the norm in the general population. The next model
of pathogenesis (and Dx-AD criteria) needs to take
this into account such questions as: 1) how do several
pathologies interact with each other in pre and clinical
phases; and 2) how do they all contribute to symptom
development?
Currently, there is growing recognition that the neurobio-
logical processes associated with AD syndrome start many
years before the appearance of any measurable clinical signs
or impairments of function. Thus, the new challenge for for-
mulating future revisions to the Dx-AD criteria is to move
the bar for discriminating the affected from unaffected
on into the unknown territory of identifying asymptomatic
people at elevated risk for the disease in the preclinical
stages. The primary Achilles heel for the future revision
of the criteria will be the accuracy or utility of current model
of pathogenesis and conceptual model of the syndrome.
255
The field is ready now to consider different conceptual
models for neurodegenerative diseases (e.g., System Fail-
ure Model for Complex Disease of the Brain). The core
premise for such a shift in thinking is based on the proposition
that the expression of key clinical features in neurodegener-
ative diseases (e.g., impairments in memory, movement or
mood) are a reflection of a systems failure, of a complex neu-
ral network, rather than due to a single etiologic factor. This
type of a model for the pathogenesis of the disease requires
a drastic shift in research and development priorities beyond
the problems of protein cleavage and aggregation.
Thus, the validation of such conceptual model, of a com-
plex disease/syndrome such as AD, will rely on developing
multiple strategies aimed at preserving/maintaining the func-
tionality of the system. In the case of AD the system
could be defined by the synaptic functionality or viability
of a neuronal network or global malfunction of well-defined
anatomical structure. The operational framework for such
a model does not rely on a single etiologic factor. Rather,
this embedded-set model approach requires understanding
the functional relationships among key components of a sys-
tem and identifying approaches to optimize the functioning
of the overall system by examining the character of its consti-
tutive components. Present notions about the neurobiology of
dementia, which have enjoyed nearly universal acceptance
during the last three decades, have proven to be inadequate
in providing effective targets for treating complex disease.
One explanation for the lackluster performance of current
drug development paradigms might be the failure of the pre-
vailing ideas about the pathogenesis of the disease to provide
a complete account of relationship between the clinical
and biological phenotypes of the disease. The current revi-
sion of the criteria was largely based on the prevailing con-
ceptual model of dementia/AD, which is increasingly being
questioned and found to be inadequate.
Future revisions of the criteria, especially when intended
to promote trials for prevention, will require the adoption of
new thinking (or models) about the full spectrum of patho-
genesis. The new models need to: 1) fully incorporate the
temporal lag between the initiating pathological event and
the first appearance of symptoms; 2) provide complete [or
better] explanations for the biological underpinnings of the
key clinical features of the disease (e.g., loss of memory
and overall deterioration of cognitive functions); and 3)
identify new or different therapeutic target.
Zaven S. Khachaturian
Editor-in-Chief*
Alzheimers & Dementia: The Journal of the
Alzheimers Association
President, Campaign to Prevent Alzheimers Disease
by 2020 [PAD2020]
Rockville, MD, USA
*Corresponding author: Tel.: 301-309-6730
Fax: 301-309-6724
E-mail address: adj@kra.net
256 Z.S. Khachaturian / Alzheimers & Dementia 7 (2011) 253256

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