SPECIAL REPORT

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Mild cognitive impairment definitions:

more evolution than revolution

Eugene YH Tang*,1, Carol Brayne2, Emiliano Albanese3 & Blossom CM Stephan1

Practice points
Background
●● There has been a lot of research and interest in intermediate cognitive states between optimal cognition and
dementia. This has resulted in evolving and diverse definitions of mild cognitive impairment (MCI) that are clinically
difficult to use.
●● Definitions of MCI can be broadly classified into either phenotype specific (mainly for Alzheimer’s Disease [AD]) or
nonphenotype specific (all-cause dementia).
●● Definitions of currently used subtypes of dementia, particularly AD, keep changing.
New definitions
●● Recent definitions by the International Working Group and the National Institute on Aging and the Alzheimer’s
Association have focused on the incorporation of biomarkers (cerebrospinal fluid and PET) in their diagnosis of AD
associated MCI.
●● Identification of those at risk of AD remains within research only and has yet to be proven of value to patients.
●● New Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria have termed MCI as a minor
neurocognitive disorder, which crucially can revert back to normal cognition.
Future work
●● Accurate identification will be required if future intervention strategies are to be employed to either delay or prevent
progression to dementia.

SUMMARY Early identification of those at higher risk of dementia may play a part
in secondary prevention and has received great clinical and research interest. Mild
cognitive impairment (MCI) is a construct originally proposed to identify those who fall
between normal cognitive aging and dementia. Clinical and research utility and validity
of MCI are hotly debated. New MCI criteria proposed include the recent construct of mild
neurocognitive disorder in the 5th edition of the Diagnostic and Statistical Manual of Mental
Disorders, MCI criteria proposed by the National Institute on Aging-Alzheimer’s Society and
criteria elaborated by the International Working Group. This article aims to discuss whether
these definitions provide clearer conceptualization of MCI and to highlight implications for
research.

1
Institute of Health & Society, Newcastle University, Newcastle upon Tyne, UK
2
Department of Public Health & Primary Care, Cambridge University, Cambridge, UK
3
Department of Psychiatry, School of Medicine, University of Geneva, Switzerland
*Author for correspondence: e.y.h.tang@newcastle.ac.uk part of

10.2217/NMT.14.42  © 2015 Future Medicine Ltd Neurodegener. Dis. Manag. (2015) 5(1), 11–17 ISSN 1758-2024 11
Special Report  Tang, Brayne, Albanese & Stephan
KEYWORDS  Much research has focused on early clinical diag-
• Alzheimer’s disease
• biomarkers • criteria
• dementia • diagnosis
• mild cognitive impairment
• prevention
12
nosis of dementing disorders in order to develop
and test interventions that might reduce or delay
the morbidity and dependence associated with
declining cognitive function. Various research
groups have tried to identify at what point pri-
mary or secondary interventions may be of use
to slow the progression to dementia in mini-
mally symptomatic subjects. In order to achieve
this, numerous definitions have been proposed
to describe what might differentiate so called
‘healthy’ or ‘normal’ aging from states that herald
dementia onset. The current widely used term is
mild cognitive impairment (MCI) [1,2] , although
many such efforts and labels p­receded this.
MCI was first introduced over 20 years ago
by Reisberg et al. [3] to describe the intermediate
stage between normal cognition and dementia.
It is thought that this stage could be a target
of meaningful interventions to delay the clini-
cal onset of impending dementia. The concept
of MCI was further refined in 1999 [4] . Here,
MCI was defined as a state where individuals
have subjective and objective memory impair-
ment that is inconsistent with age but normal
physical functioning and performance in non-
memory cognitive domains. The main focus of
these criteria was to detect memory problems
due to prodromal Alzheimer’s disease (AD).
However, upon further investigation it was clear
that not all forms of MCI evolve into dementia
(e.g., clinically diagnosed AD) and that broader,
more inclusive clinical criteria were required.
In 2003, an international group of dementia
researchers developed consensus criteria and
expanded the definition of MCI to include objec-
tive and subjective impairments in any cognitive
domain [5] . The Mayo Clinic criteria were also
similarly expanded [6] . Subclassifications of MCI
were created depending on the nature of the cog-
nitive domain impaired, for example, amnestic,
no­namnestic and multidomain phenotypes.
The continuing evolution of the MCI concept
reflects not only the intensity of clinical research
in this field but also the recognition that those
definitions did not work that well nor do they
clearly identify many who are not at risk within
a reasonable period. Indeed, different definitions
and operationalization of MCI lead to highly
variable incidence and prevalence estimates [7,8]
as with dementia itself. Although a higher pro-
portion of those with MCI generally progress
to dementia compared with cognitively intact
individuals [9,10] , the annual ‘conversion’ rate is
Neurodegener. Dis. Manag. (2015) 5(1)
still relatively low, 5–10% in community-based
samples [11] and 10–15% in some specialist clin-
ics [11,12] . Some studies have reported reversion
to normal cognitive function of those who met
MCI criteria at rates of around 30% per year [10] .
Refinements and revisions of the original
MCI criteria have been proposed. However,
the validity of MCI and its utility both in
clinical and research settings remain unproved
and debated. As more recent definitions have
attempted to address the numerous conceptual
and practical issues related to the initial MCI cri-
teria (see Table 1 for a description of the inclusion
and exclusion criteria for each new definition),
it is important to explore the extent to which
these definitions may provide an opportunity for
a substantial improvement in the field and the
implications these revisions might have.
Issues & limitations of MCI
Large variability exists in the operationalization
of MCI including: the defining criteria used; the
implementation of criteria (e.g., cognitive tests);
sources of samples (e.g., clinical vs community-
based, volunteers vs population); and standard
thresholds to define impairment with reference
to normative data [13] . Moreover, with the evo-
lution of MCI criteria they now have a higher
ability to identify people at earlier stages of par-
ticular subtypes; pure amnestic MCI intended
for AD, and nonamnestic MCI for vascular
dementia (VaD) [14] . However, MCI criteria
need to remain broad to be inclusive of a large
range of possible future diagnoses. An etiologi-
cal understanding aims to provide the basis for
development of specific and targeted therapeutic
responses and allow prediction of specific lon-
gitudinal clinical trajectories. At present MCI
encompasses a variety of potential underlying
physiopathological processes and lacks clear
b­iological underpinnings.
Diagnostic & statistical manual for mental
disorders 5th edition criteria for MCI
The recent update of the diagnostic and statisti-
cal manual for mental disorders (DSM) 5 has a
subsection on neurocognitive disorders (NCDs)
[15] . This replaces the DSM-IV category of ‘delir-
ium, dementia and amnestic and other cogni-
tive disorders’ differentiating between major
and mild disorders. Crucially, mild NCD may
or may not progress to major NCD. The crite-
ria for mild NCD resemble the expanded Mayo
Clinic criteria and aim to clarify the extent of
future science group

Table 1. Diagnostic criteria for mild cognitive impairment.
Definitions Terminology for MCI Requirements
Mayo Clinic MCI
   
   
   
   
Fifth Edition of the Diagnostic Mild neurocognitive
and Statistical Manual of Mental disorder
Disorders
   
   
   
International Working Group Prodromal AD
Criteria
   
   
National Institute on Aging- MCI
Alzheimer’s Association Workgroup
  MCI due to AD
   
   
   
   
   
   
 Aβ1–42: Amyloid β1–42; AD: Alzheimer’s Disease; MCI: Mild cognitive impairment.
cognitive impairment prior to defining the eti-
ology of the impairment. Further, unlike other
definitions which subclassify MCI by the degree
of memory impairment, the diagnosis of mild
NCD does not differentiate between amnes-
tic and nonamnestic components. Limitations
include reference to objective neurocognitive
assessment without further specification and it
is defined by a noticeable loss of normal cogni-
tive functioning, which requires the individual
to compensate to maintain his/her independence
and remain able to perform activities of daily
living, but these activities are not specified [16] .
The DSM 5 definition of mild neurocogni-
tive disorder captures both amnestic and non-
amnestic subtypes of MCI. A recent prevalence
study of those aged ≥55 years, comparing Mayo
Clinic MCI and DSM 5 criteria for mild NCD
found that the weighted prevalence was 7.93 and
3.72%, respectively [17] . The lower prevalence
future science group
Mild cognitive impairment definitions  Special Report
Subjective memory complaint either from the patient or reliable informant
Normal cognitive function
Objective memory impairment
Preserved activities of daily living
No dementia
Noticeable cognitive decline from a previous level of performance in one or
more cognitive domains) raised by the patient or an informant or observations
made by a clinician
Cognitive impairment doesn’t interfere with independence or activities of daily
living
Cognitive symptoms are not due to delirium
No dementia
Amnestic syndrome of the hippocampal type (Free and Cued Selective
Reminding Test) specifically recommended).
One or more positive in vivo evidence of Alzheimer’s pathology in either
cerebrospinal fluid (decreased Aβ1–42) together with increased T-tau or P-tau or
in PET with increased tracer retention on amyloid
Absence of dementia
Concern regarding cognitive a change in cognition (individual, informant who
knows them well or clinician)
Cognitive impairment in one or more domains
Preservation of independence in functional abilities
No dementia
Positive or negative on biomarkers reflecting neuropathology (Aβ protein) and/
or neuronal injury
High likelihood: positive Aβ protein and neuronal injury biomarker.
Intermediate likelihood: positive Aβ protein biomarker (neuronal injury
biomarker not tested) OR positive biomarker of neuronal injury (Aβ biomarkers
not tested)
Unlikely: negative biomarkers for both Aβ and neuronal injury
may be partially explained by both the stringent
criteria for cognitive deficit in DSM 5 and by the
exclusion of psychiatric disorders such as depres-
sion known to be associated with cognitive
impairment [17] . Irrespective of the proportion
of any population meeting particular criteria,
longitudinal studies with careful operationaliza-
tion of the suggested criteria are awaited to assess
the ability of DSM 5 to predict future dementia.
Mild cognitive impairment due to
Alzheimer’s disease
Two new sets of criteria for AD have been
recently published by the International Working
Group (IWG) [18] and the National Institute
on Aging and the Alzheimer’s Association
(NIA-AA) [19] . Both sets of criteria incorporate
biomarkers and cognitive impairment. They dif-
fer in terms of approach, terminology and the
use of b­iomarkers [20] .
www.futuremedicine.com 13
Special Report  Tang, Brayne, Albanese & Stephan
International working group criteria
for MCI
To address the issue of underlying etiology and
MCI classification, the concept of ‘prodromal
AD’ was first introduced in 2000 [21] . In 2007,
the IWG for New Research Criteria for the
Diagnosis of AD introduced biomarkers into the
core diagnostic framework [22] . This included
structural magnetic resonance imaging, molecu-
lar neuroimaging with PET and cerebrospinal
fluid (CSF) analysis. This addition aimed to
enable AD to be diagnosed in the prodromal
stage and make those in any population who
meet these criteria a more homogeneous group.
The IWG framework views AD and indeed
other specific subtypes as a disease continuum
with a single set of criteria applicable to all stages
of the disease. As the pathological processes pre-
cede symptoms, this was further refined in 2010
to draw a distinction between clinical manifesta-
tion and disease pathology, the former being set as
the onset of clinical dementia [23] . This distinction
also broadened the preclinical spectrum of AD.
Two states were defined: asymptomatic at-risk
state for AD (no clinical signs/symptoms but bio-
markers of AD pathology) and presymptomatic
AD (carrying an autosomal dominant monogenic
AD mutation with virtually full p­enetrance) [23] .
The IWG have recently proposed revisions
for preclinical states of AD [18] . This requires the
absence of clinical symptoms of AD, the presence
of at least one biomarker of AD pathology to iden-
tify the asymptomatic at-risk state or the presence
of a proven AD autosomal dominant mutation
to diagnose the presymptomatic state. Biomarker
support includes in vivo evidence of AD patho-
physiology, which is defined as increased brain
amyloid retention on PET imaging or decreased
amyloid β1–42 together with increased T-tau or
P-tau in the CSF [18] . The subsequent combi-
nation of a specific cognitive profile consistent
with either typical or atypical AD phenotype, in
addition to a positive pathophysiological marker
moves the individual into the ‘prodromal AD’
state, in other words, fulfills biomarker criteria
in the absence of c­linical dementia.
National Institute on Aging & the
Alzheimer’s Association diagnostic criteria
In 2011, the NIA-AA proposed revisiting the
criteria to diagnose AD [19] . This built on the
proposal from the IWG criteria from 2007. The
NIA-AA criteria and recommendations labeled
the symptomatic predementia phase of AD as
14 Neurodegener. Dis. Manag. (2015) 5(1)
MCI. A change from previous MCI criteria is
the acceptance that functional losses may still
occur even whilst maintaining a sufficient level of
independence. The NIA-AA working group on
MCI proposed the following core clinical criteria:
concern regarding a change in cognition from
the patient, informant, clinician; impairment in
one or more cognitive domains; preservation of
independence in functional abilities; and, not
demented [24] . Memory impairment is not neces-
sary for diagnosis and MCI, similar to the Mayo
Clinic criteria set out in 2004 [6] .
Biomarkers have also been incorporated when
the diagnosis is MCI due to AD, which assumes
that AD is a single entity – which may work for
younger dementia but perhaps not so well for older
individuals with dementia (e.g., who are more
likely to show mixed pathology). The NIA-AA
criteria make a distinction between markers that
directly reflect AD pathology – β-amyloid pro-
tein and tau and less direct markers of AD, for
example, neuronal injury markers [24] . If an indi-
vidual meets core clinical criteria for MCI and
has either a positive amyloid or neuronal injury
biomarker then the MCI is termed MCI due to
AD – intermediate likelihood. If both amyloid
and neuronal injury biomarkers are positive then
they are termed MCI due to AD – high likeli-
hood. If biomarkers have been obtained in the
context of MCI and considered uninformative,
the diagnosis of MCI will still apply although will
be termed MCI – unlikely due to AD.
The distinction in amyloid and neuronal
injury is useful as is the broad definition of cog-
nitive impairment which is inclusive of nonam-
nestic MCI. However, the weight of amyloid and
neuronal injury seems to be equal in diagnosis,
which is contrary to the amyloid cascade hypoth-
esis where amyloid pathology heralds the start of
AD and neuronal injury is a secondary phenom-
enon [25] . This meaning that in theory amyloid
biomarkers will have a higher sensitivity for AD
than neuronal injury, whereas injury markers will
have a higher specificity [20] .
Limitations of new criteria
Difficulties in the application of new criteria
include the lack of robust validation, the cost
and acceptability of PET and CSF analysis. Nor
are there well defined cut offs for the different
biomarkers [26] , a prerequisite of validity yet to
be demonstrated despite widespread uptake. Not
all centers will have access to PET scanning and
expertise and variable acceptability of lumbar
future science group

punctures for CSF analysis, which may have
adverse effects and very rare serious complica-
tions. Risk–benefit profiles need to be assessed,
across countries and cultures as well as the ethical
implications [27] . Cost–effectiveness studies will
be required to assess the feasibility and practi-
cality of implementing such strategies in MCI
individuals who may or may not evolve to AD.
Few studies have been done in dementia research
of the clinical utility of novel tests including bio-
markers, imaging and neuropsychology. Further,
although the strength of preclinical and prodro-
mal AD are useful in identifying those at risk of
symptomatic AD, non-AD conditions make up
over half of the dementia syndrome [28] . MRI
and relevant investigations are still required to
identify non-AD pathology and reassurance of
negative a preclinical/prodromal AD state does
not mean the individual is not at risk of non-
AD dementia. Caution should also be adopted
in labeling an individual as MCI due to AD,
particularly as many will not develop AD itself
or might develop non-AD dementia.
Role of biomarkers
The translation of biomarker studies into guide-
lines for AD diagnosis has come from studies
suggesting high specificity of CSF biomarkers
and PET amyloid imaging has for AD [29] . It
seems useful to rank biomarkers, as per NIA-AA
recommendations, to diagnose and possibly
identify an individual’s eventual prognosis with
better certainty, as many individuals who are
biomarker positive do not convert to sympto-
matic dementia. One study found that individu-
als who received a diagnosis of AD had decreased
levels of CSF amyloid [30] at least 5–10 years
before conversion from MCI, whereas tau pro-
teins are reported to be later markers [31] . Injury
markers have been associated with accelerated
rates of progression. For example, a combination
of high CSF tau without a proportional increase
in p-tau 181 has been reported to be associ-
ated with a faster rate of cognitive decline [32] .
However, research studies are limited and fur-
ther work investigating the temporal sequence
of biomarkers and their predictive accuracy is
needed, particularly in representative samples.
Implications for research
The evolving concept of MCI highlights both
the challenge of attempting to single out groups
for whom a specific intervention might be of val-
uable importance within this cognitive spectrum
future science group
Mild cognitive impairment definitions  Special Report
and the intensity of research in this area. At pre-
sent, use of both IWG and NIA-AA criteria are
recommended for research only. There are argu-
ments both for and against diagnosing MCI spe-
cifically in the context of AD (NIA-AA, IWG)
and in the context of dementia (not otherwise
specified; DSM 5, Mayo Clinic Criteria). There
have also been attempts to better refine MCI cri-
teria; for example, by differentiating levels (early
vs late MCI determined by the presence/absence
of memory impairment in combination with
subjective concern) [33] .
The two-step procedure adopted in the
DSM 5 and original Mayo Clinic criteria
requires the initial classification of the indi-
vidual as having cognitive impairment prior to
determining etiology. This is to capture a greater
number of individuals with subjective memory
impairment under the umbrella term of MCI,
with the limitation that a lower proportion of
those identified will progress to dementia, which
is the overall aim. Further, unlike NIA-A and
IWG diagnosed MCI individuals, the etiologi-
cal basis of their memory impairment would be
unknown.
Diagnosis of MCI encompassing all levels
of severity in general clinical practice would be
inappropriate as there are no preventive treat-
ments. It may be more beneficial to identify sub-
groups (rather than subtype) in MCI, focused
on those with a greater chance of conversion. A
recent study in primary care found that within
a 3 year period currently defined MCI subtypes
were not good at predicting the course of MCI.
Instead, the ability to learn new material (meas-
ured by the Consortium to Establish a Registry
for AD) has been identified as differentiating
between remittent and progressive MCI [34] .
Depressive symptoms also seem to be associated
with the severity of MCI [34] . This may also be
gender specific as although depressive symptoma-
tology increases MCI progression in women, the
risk of stroke has been found to be associated
with progression in men [34] . Risk stratification
by gender and introducing specific intervention
programs, for example, stroke prevention for
men and talking therapies for women could be
explored.
Ethical implications
The lack of certainty of outcome and treatment
(for memory impairment and dementia) has
resulted in several ethical dilemmas associated
with MCI. This includes for example, disclosure
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Special Report  Tang, Brayne, Albanese & Stephan

(the dilemma between the patient’s right to
know and wish to avoid harm) and how a diag-
nosis of MCI may stigmatize an individual and
affect his/her quality of life (and also insurance
applications and issue of living arrangements)
[35] . Further education and research in this area
is needed particularly as MCI progresses and
is incorporated into every day clinical practice.
Given the current lack of interventions for demen-
tia or MCI, discussions with individuals and their
family must to be sensitive and realistic in terms
of the heterogeneous course, uncertainty in out-
comes and indeed of its value at all. However,
there may be opportunities to improve dementia
secondary prevention (i.e., delay the progression
of MCI to dementia itself) through improved
lifestyle and better control of vascular risk factors.
Conclusion & future perspective
Research into the created concept of MCI has
grown at a rapid rate in both phenotype and
nonphenotype specific criteria. Ultimately, the
goal of any MCI construct should be to alter
the natural history through the identification
of those at greater risk, so that individually
tailored prevention strategies to delay progres-
sion of cognitive impairment can be delivered to
individuals who could benefit the most.
It is clear that before research findings can be
translated into clinical practice further impor-
tant advancements are needed to address the
existing imbalance between the conceptual
and operational substance of MCI definitions.
Although extreme caution will be needed to
interpret the awaited results from clinical trials
currently being conducted in participants with
MCI, this evidence may provide an unexpected
opportunity to disentangle some of the pending
issues of the current MCI definitions.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a finan-
cial interest in or financial conflict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending or royalties.
No writing assistance was utilized in the production of
this manuscript.

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