Ageing Research Reviews 20 (2015) 1–10

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Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr

Review

Cognitive frailty, a novel target for the prevention of elderly

dependency
Ruan Qingwei a,b , Yu Zhuowei a,b,c,∗ , Chen Ma a,b , Bao Zhijun b , Li Jin c , He Wei d
a
Shanghai Institute of Geriatrics and Gerontology, Shanghai 200040, China
b
Research Center of Aging and Medicine, Shanghai Key Laboratory of Clinical Geriatrics, Huadong Hospital, Shanghai Medical College, Fudan University,
Shanghai 200040, China
c
Department of Geriatrics, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
d
PET-CT Center, Department of Nuclear Medicine, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China

a r t i c l e i n f o a b s t r a c t

Article history: Frailty is a complex and heterogeneous clinical syndrome. Cognitive frailty has been considered as a sub-
Received 11 October 2014 type of frailty. In this study, we refine the definition of cognitive frailty based on existing reports about
Received in revised form frailty and the latest progress in cognition research. We obtain evidence from the literature regarding
12 December 2014
the role of pre-physical frailty in pathological aging. We propose that cognitive impairment of cogni-
Accepted 16 December 2014
tive frailty results from physical or pre-physical frailty and comprises two subtypes: the reversible and
Available online 30 December 2014
the potentially reversible. Reversible cognitive impairment is indicated by subjective cognitive decline
(SCD) and/or positive fluid and imaging biomarkers of amyloid-␤ accumulation and neurodegenera-
Keywords:
Cognitive frailty
tion. Potentially reversible cognitive impairment is MCI (CDR = 0.5). Based on the severity of cognitive
Physical frailty impairment, it is possible to determine the primary and secondary preventative measures for cognitive
Pre-physical frailty frailty. We further determine whether SCD is a component of pre-clinical AD or the early stage of other
Pre-MCI neurodegenerative diseases, which is required for guiding personal clinical intervention.
Subjective cognitive decline © 2014 Elsevier B.V. All rights reserved.
Pre-clinical AD

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. The rationale for cognitive frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.2. Chronological order between physical frailty and cognitive impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.3. Support for pre-physical frailty as a cause of cognitive frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.4. Cognitive frailty and MCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.5. Cognitive frailty and SCD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3. The suggested definition of cognitive frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4. The possible mechanisms of cognitive frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
5. The proposed tools to measure reversible cognitive frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
6. The prevention of cognitive frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

1. Introduction

∗ Corresponding author at: Huadong Hospital, Shanghai Medical College, Fudan

Aging is the progressive and overall physiological decline of
University, 221 West Yan An Road, Shanghai 200040, China. Tel.: +86 21 62483180;
the reserves of an organism, which decreases the ability to gen-
fax: +86 21 62484981. erate adaptive responses and sustain homeostasis. Consequently,
E-mail address: qingweir@aliyun.com (Z. Yu). the body becomes more susceptible to stress, diseases and injuries.

http://dx.doi.org/10.1016/j.arr.2014.12.004
1568-1637/© 2014 Elsevier B.V. All rights reserved.
2 Q. Ruan et al. / Ageing Research Reviews 20 (2015) 1–10
The loss of essential body functions leads to age-related patholo-
gies, which ultimately lead to death (López-Otín et al., 2013;
Moskalev et al., 2014). Diseases accelerate aging, thereby dimin-
ishing the body’s adaptation via the relevant stress responses.
Multiple subclinical and age-related comorbidities in the elderly
may exacerbate the decline in the physiological reserves of several
systems, which would then result in a homeostatic imbalance or
frailty (Clegg et al., 2013). Aging compromises the adaptive stress
responses of an organ or the body to external stimuli, such as the
ability to adapt in response to abrupt changes in health conditions.
Frail elderly individuals display a greater apparent vulnerability to
minor diseases in that this population often has difficulty in retur-
ning to baseline equilibrium after mild stressors (Clegg et al., 2013;
Ferrucci et al., 2002). Frailty is a pathological aging process that is
reversible and occurs at an intermediate stage between age-related
diseases and a poor prognosis, such as disability or death (Moeley
et al., 2013; Clegg et al., 2014; Dorner et al., 2013; Tavassoli et al.,
2014). In other words, early intervention can improve the patient’s
quality of life and reduce the adverse health consequences for the
patient, thereby achieving the goal of healthy aging.
Based on different pathogeneses, frailty can be divided
into physical frailty, cognitive frailty and psychosocial frailty
(Malmstrom and Morley, 2013; Panza et al., 2011). A broad con-
sensus has been reached for the definition of physical frailty,
which manifests as a reduction in body strength, stamina and
physiological functions, which in turn, leads to an increased possi-
bility of physical vulnerability, disability and death (Moeley et al.,
2013). Typically, physical frailty is suggested when at least three
of the five following criteria are present: fatigue, decreased mus-
cle strength, low walking speed, reduced physical activities and
unintentional weight loss; pre-physical frailty is determined by
the presence of one or two of the five criteria (Moeley et al.,
2013). Cognitive frailty was proposed by Panza et al. (2006) when
these authors examined the risks of decreased cognitive functions
modulated by vascular factors. Subsequent studies revealed that
physical factors and cognition are crucial elements in predict-
ing risk of death (Panza et al., 2006, 2011; Pilotto et al., 2012).
To differentiate cognitive impairment not dementia (CIND) in
the absence of physical frailty, a consensus on the definition of
cognitive frailty was reached by the International Academy on
Nutrition and Aging and the International Association of Gerontol-
ogy and Geriatrics in April, 2013 (Kelaiditi et al., 2013). Although
the emergence of cognitive frailty reflects a verifiable improve-
ment in preventing a poor prognosis of aging, many experts in
the field have provided beneficial suggestions for clarifying the
definition of cognitive frailty (Woods et al., 2013; Buchman and
Bennett, 2013; Dartigues and Amieva, 2014). Based on physical
weakness and cognitive impairment, especially in light of the lat-
est consensus arising from studies of subjective cognitive decline
(SCD) and fluid and imaging biomarkers of amyloid-␤ accumula-
tion and neurodegeneration, we herein refine the framework for
the definition and potential mechanisms of cognitive frailty, as well
as relevant screening tools. Furthermore, we explore the signifi-
cance of our suggestions in preventing the progression of cognitive
frailty.
2. The rationale for cognitive frailty
2.1. Overview
The physical phenotype of frailty and cognitive impairment has
an obvious interrelationship. During the aging process, the inter-
action of physical frailty and cognitive impairment causes a cycle
of physical and cognitive functional decline and poor quality of
life (Houles et al., 2012; Robertson et al., 2013; Han et al., 2014;
Shimada et al., 2013; Mhaoláin et al., 2012; Buchman et al., 2007,
2008). Comorbidities and physical frailty are often found in patients
with Alzheimer’s disease (AD) and are closely related to the het-
erogeneity and clinical manifestations of this disease (Oosterveld
et al., 2014). Physical frailty, combined with cognitive impairment,
is predictive of an increased risk of a poor prognosis. In other
words, the phenotypic integration of cognitive impairment and
frailty clearly improves the predictive effectiveness of the latter
regarding a poor prognosis in a 4-year follow-up of elderly subjects
(in which the top five categories include death, disability, enter-
ing a nursing facility, hospitalization and a fall) (Rockwood, 2005;
Avila-Funes et al., 2009; Cano et al., 2012; Kulmala et al., 2014).
Cognitive frailty refers to the heterogeneous clinical syndrome
that is found in elderly individuals, excluding those with AD and
other dementias, that is characterized by concurrent physical frailty
and potentially reversible cognitive impairment (Clinical dementia
rating score (CDR) = 0.5) (Kelaiditi et al., 2013). This implies that
cognitive frailty is a form of pathological brain aging and a precur-
sor to neurodegenerative processes. Physical frailty and cognition
are associated, however, the causal links between physical frailty
and cognitive impairment are not clear. The aim of the consensus
group is to establish a conceptual framework for the study of cogni-
tive impairment in individuals due to physical reasons (including a
psychological component resulting from physical impairment), but
not due to the presence of a concomitant neurological disease. The
significance of this definition lies in providing a novel target for sec-
ondary prevention to stem elderly disability. However, developing
a definition requires a number of challenges to be addressed before
the definition can be promoted clinically and used in future. In this
article, we discuss the specific issues that are useful for clarifying
the definition and research criteria for cognitive frailty in medical
practice and clinical research.
2.2. Chronological order between physical frailty and cognitive
impairment
Because the underlying mechanisms for the physical impair-
ment due to cognitive decline are well known, the consensus group
hopes to explain a cognitive decline caused by physical conditions
or factors independent of neurodegenerative conditions. However,
a consensus on the definition of cognitive frailty requires the simul-
taneous presence of both physical frailty and cognitive impairment
(CDR = 0.5) (Kelaiditi et al., 2013). Thus, there may be confusion in
designing clinical experiments. If physical frailty is present before
cognitive impairment occurs, researchers of cognitive frailty should
recruit individuals with only physical frailty to carry out a lon-
gitudinal study. Although a cross-sectional study design would
be appropriate when both physical frailty and cognitive impair-
ment (CDR = 0.5) are present, the subjects in the study may include
individuals whose physical impairment may result from cognitive
decline (CDR = 0.5). About one-third of mild cognitive impairment
(MCI) patients experience obstacles in the instrumental activities
of daily living (Morris, 2012). Moreover, these cognitively frail indi-
viduals can also be referred to as physically frail individuals with
MCI (CDR = 0.5).
2.3. Support for pre-physical frailty as a cause of cognitive frailty
A growing body of research evidence supports connections
between frailty, cognitive impairment and dementia. It has been
shown that cognitive frailty can be a prelude to degenerative neu-
rological diseases and that physical frailty can enhance the future
risk of MCI and dementia in cognitively normal populations, as
well as accelerate the cognitive impairment of these individuals
(Boyle et al., 2010; Buchman et al., 2007; Auyeung et al., 2011).
Physical frailty can augment the risk of delirium and death in
 Q. Ruan et al. / Ageing Research Reviews 20 (2015) 1–10
Fig. 1. The components of cognitive frailty and different trajectories of both physical and cognitive functions under specific conditions.
hospitalized elderly individuals (Eeles et al., 2012). Studies have
revealed that cognitive impairment is secondary to a plethora of
illnesses, such as age-associated health problems, heart disease,
hypertension, stroke, diabetes, chronic kidney disease, viral infec-
tions (e.g., HIV and hepatitis C) and substance use (Oosterveld
et al., 2014; Knopman and Roberts, 2010; Devlin et al., 2012;
Hayden et al., 2010; Weiner and Seliger, 2014). In addition, an
age-associated decline in health status is also a risk factor of AD
and dementia (Song et al., 2011). The severity of physical frailty
can be evaluated by adopting a numerical score or studying a
dynamic state over time (Puts et al., 2005a; Moeley et al., 2013;
Tavassoli et al., 2014; Pilotto et al., 2012; de Vries et al., 2011,
2012; Bouillon et al., 2013; Ng et al., 2014). It was reported that
elderly subjects with physical frailty did indeed have a signifi-
cantly higher degree and percentage of cognitive impairment than
those displayed by elderly individuals who were robust and had
pre-physical frailty. Additionally, the elderly subjects with physical
frailty combined with cognitive impairment exhibited even higher
rates of disability (Avila-Funes et al., 2009). A longitudinal study
with an average duration of five years revealed that mild physi-
cal impairment (according to a performance-based assessment) in
cognitively normal elderly adults might lead to cognitive decline,
which could later be clinically detected and was closely associ-
ated with the development of dementia due to AD (Wilkins et al.,
2013). The clinical manifestations of physical frailty also display an
apparent hierarchy. Weakness is the earliest emerging condition of
pre-physical frailty and, during this stage, the presence of slowness,
reduced activity/exhaustion and weight loss indicates a rapidly ris-
ing risk of pre-physical frailty transforming into physical frailty
(Xue et al., 2008) (Fig. 1). Frailty is a process of dynamic transforma-
tion. Based on clinical, functional, behavioral and biomarker-based
differences, even pre-physical frailty is clearly different from nor-
mal aging and is part of a pathological aging process (Abellan van
Kan et al., 2008). Therefore, prompt intervention can achieve a bet-
ter outcome, and pre-physical frailty has already become a target
for primary prevention (Abellan van Kan et al., 2008). Addition-
ally, a question has been raised as to whether pre-physical frailty
in patients should be incorporated as a physical factor contributing
to cognitive frailty (Dartigues and Amieva, 2014). We propose here,
that clinical pre-physical frailty should be adopted as a diagnostic
criterion of cognitive frailty.
3
2.4. Cognitive frailty and MCI
A major controversial point regarding the definition of cognitive
frailty is reversible cognitive impairment (CDR = 0.5), which can
be fairly confusing. It was proposed that a CDR value of 0.5 was
equivalent to the MCI stage (Hughes et al., 1982; Morris, 1993).
On one hand, this criterion makes it difficult to discriminate cog-
nitive frailty from MCI, prodromal period AD and CIND; on the
other hand, progressive neuronal cell loss during the MCI stage
may surpass the physiological ability of the brain to compensate;
thus, irreversible cognitive damage might have already occurred
(Gomez-Isla et al., 1996; Aisen, 2008). Based on the neuropsychol-
ogical profile, MCI is divided into three subtypes: amnestic MCI
is considered to progress preferentially to AD; MCI with a slight
impairment of multiple cognitive domains may progress to either
AD or vascular dementia or be part of the normal cognitive aging
process; and single-domain non-memory MCI may progress to
non-AD dementia (Portet et al., 2006). Some MCI patients have
symptoms that are reversible and can recover to regain normal
cognitive function. The cognitive functions of other patients may
even be stable and not change throughout the remainder of their
lives. However, more MCI patients exhibit an irreversible, pro-
gressive reduction in cognition (Golomb et al., 2004; Matthews
et al., 2008; Mitchell and Shiri-Feshki, 2009). In the early stage of
cognitive decline, cognitively impaired individuals often display a
functional loss in more complicated tasks (e.g., instrumental activi-
ties of daily living), whereas the functional loss of simpler tasks (i.e.,
activities of daily living) appears in the more severe stage of cogni-
tive impairment (Millán-Calenti et al., 2012; Njegovan et al., 2001;
Barberger-Gateau et al., 1992). Studies have revealed that 34% of
MCI patients experience obstacles in performing the instrumental
activities of daily living (e.g., managing the household economy),
and this percentage is significantly higher than that (5%) of non-
MCI populations (Morris, 2012). According to the definition, the
appearance of physical disabilities is clearly not a component of
physical frailty. Previous studies indicated that immunotherapy-
based clinical trials involving humanized monoclonal antibodies
against amyloid ␤ peptide, bapineuzumab and solanezumab, failed.
Moreover, in a 5-year comparative study, Ginkgo biloba extract and
a placebo were used as agents of intervention to examine a large
cohort of subjective cognitive impairment and/or MCI subjects
4 Q. Ruan et al. / Ageing Research Reviews 20 (2015) 1–10
(2854 individuals); the results revealed that Ginkgo biloba extract,
a potent antioxidant, could not reduce the risk of progression of
impairment in AD patients. A lesson learned from these studies
is that the target (cognitive impairment in the study subjects) of
secondary prevention should be a focus in pre-clinical AD or asymp-
tomatic AD (Doody et al., 2014; Vellas et al., 2012, 2013). At the
asymptomatic stage, patients have produced in vivo signals (e.g.,
positive for certain biomarkers) that are indicative of their brain
diseases (Sperling et al., 2011, 2013; Caselli and Reiman, 2013).
2.5. Cognitive frailty and SCD
Recently, the Subjective Cognitive Decline Initiative (SCD-I)
Working Group formulated a basic conceptual framework for the
study of the common concepts of SCD, pre-MCI SCD and SCD
in pre-clinical AD (Jessen et al., 2014). SCD refers to a type of
cognitive decline in which, although the subjects have altered
subjective cognitive function, including subjective memory dys-
function or other types of deterioration in subjective cognitive
functions (e.g., executive function, attention, language and visu-
ospatial function), the individuals display a normal performance
in cognitive testing (Fig. 1) (Jessen et al., 2014). SCD is char-
acterized by increasing compensatory cognitive efforts (normal
cognitive performance range) and subtle cognitive decline in two
phases (Fig. 1). After the subtle cognitive decline, cognitive func-
tional reserve is not sufficient to maintain normal age-, sex-, and
education-adjusted performance due to increasing brain pathol-
ogy and objective cognitive decline (MCI or prodromal AD) occurs
(Fig. 1). Therefore, in the scope of cognitive impairment onward
to the stage of dementia, SCD is a non-specific condition that
not only may appear as the first symptom of pre-clinical AD (the
asymptomatic at-risk stage of AD or pre-MCI stage of AD patients),
but may also emerge in various types of pre-MCI patients, such
as those with normal aging, certain personality traits (e.g., ner-
vousness or anxiety), an individual cultural background, non-AD
mental or neurological disorders, other diseases (e.g., cerebrovas-
cular risk factors, stroke or former head injury), and drug-abuse
(Jessen et al., 2014). Longitudinal neuropsychological assessment
can indicate the time of symptomatic conversion to MCI. The util-
ity of SCD is to pre-select subjects who may have an early cognitive
impairment before the MCI stage. The major advantages of enrich-
ment by SCD are its low cost, safety, convenience and a short
time in clinical application. However, it is noteworthy that some
subjects with reversible cognitive impairment probably do not
have SCD. These individuals could be identified by biomarkers of
both amyloid ␤-accumulation and neurodegeneration or neuronal
injury.
Cognitive impairment (CDR = 0.5) in the present definition of
cognitive frailty, obviously ignores individuals with reversible cog-
nitive impairment, such as SCD and/or positive biomarkers of
both amyloid ␤-accumulation and neurodegeneration or neuronal
injury (CDR < 0.5). If MCI (CDR = 0.5) is a potentially reversible cog-
nitive impairment, SCD and/or positive biomarkers are an early
cognitive impairment that occur before MCI and have an evidently
reversible nature. As reversible cognitive damage is clearly optimal
for serving as a secondary target for the prevention of cognitive
impairment, the level of the cognitive damage in cognitive frailty
ought to include SCD and/or positive biomarkers which are lower
than that with MCI. Because numerous causes may lead to SCD apart
from AD, we adopt the appearance of pre-MCI SCD and/or posi-
tive biomarkers, which have a relatively broad scope as diagnostic
criteria of cognitive frailty (Fig. 1) (Jessen et al., 2014). Obviously,
SCD with a clinical diagnosis of acute impairment, mental or neu-
rological diseases should be excluded as cognitive impairment of
cognitive frailty.
3. The suggested definition of cognitive frailty
Based on the above rationale, we suggest the definition of cog-
nitive frailty to be a heterogeneous clinical syndrome of cognitive
impairment (CDR ≤ 0.5) that develops in elderly individuals, is
caused by physical factors (e.g., physical frailty and pre-physical
frailty) and is excluded from dementia resulting from AD or other
conditions. Cognitive frailty includes two subtypes, reversible and
potential reversible cognitive frailty (Figs. 1 and 2). The cognitive
impairment of reversible cognitive frailty is SCD and/or positive
biomarkers resulting from physical factors. SCD and/or positive
biomarkers may occur at the late stage of pre-clinical AD or at
the pre-MCI stage due to other causes. Only SCD and/or posi-
tive biomarkers, unrelated to an acute event, clinical diagnosis of
neurodegenerative and mental conditions, are caused by physical
factors and is cognitive impairment of reversible cognitive frailty
(Fig. 1). The cognitive impairment of potentially reversible cogni-
tive frailty is MCI (CDR = 0.5), which had been discussed in detail by
the consensus group.
4. The possible mechanisms of cognitive frailty
The aging of organisms is caused by a series of complex and
interconnected events. Nutrition-sensing signals, such as growth
factors, insulin and insulin-like growth factor 1 (IGF 1), can acti-
vate mammalian target of rapamycin receptor complex 1 and
inhibit adenosine monophosphate (AMP)-activated protein kinase,
which leads to elevated activities of p53 and p16 and, in turn,
causes telomere shortening and DNA damage. As a consequence,
mitochondrial biogenesis and function decline, which then ush-
ers in a series of events, including cell senescence, stem cell
depletion, alterations in intercellular signals, disorders of the regu-
latory systems, neuroendocrine dysfunction, inflammatory aging
and immune senescence. These events collectively culminate in
the aging of the body (Fig. 2) (López-Otín et al., 2013; Sahin and
DePinho, 2013; Moskalev et al., 2014). Moreover, genetic and envi-
ronmental elements, in conjunction with epigenetic mechanisms,
lead to the accumulation of metabolic errors and molecular and
cellular damages that are manifested as excessive exogenous and
endogenous genomic injury and inadequate DNA repair. Subse-
quently, DNA exhibits a reduction in overall methylation but a
localized methylation enhancement, altered histone modification
and chromatin remodeling, which compromise protein homeo-
stasis in various pathways and trigger autophagy, proteasome
degradation, protein refolding and protein aggregation (López-Otín
et al., 2013; Moskalev et al., 2014).
Aging causes a state of increased vulnerability/susceptibility
and a gradual decrease in the physiological reserves of mul-
tiple organs, as well as pathologies associated with increased
age, such as neuroendocrine dysfunction, systemic homeostatic
mechanisms (e.g., oxidative damage, inflammation and mitochon-
drial activities), metabolic modifications, reduced physical activity,
immune senescence and aberrant apoptosis and energy production
(Wang et al., 2010; Leng et al., 2004a,b; Walston et al., 2002, 2006,
2008; Ho et al., 2011; Akki et al., 2014; Ko et al., 2012; Puts et al.,
2005b; Lang et al., 2009) (Fig. 2). In the course of aging, hormesis
can only occur when there is a sufficient level of stress responses,
which accelerate senescence and manifest as a collapse of stress-
resistance, protein denaturation or aggregation, the accumulation
of DNA mutations, mitochondrial insufficiency, dysfunctional Ca2+
homeostasis, cellular senescence and apoptosis (Moskalev et al.,
2014). When people age, the emergence of abnormalities in three
or more systems (e.g., pathophysiological modifications caused
by cardiovascular and pulmonary diseases and diabetes) may
accelerate the depletion of physiological reserves and initiate
 Q. Ruan et al. / Ageing Research Reviews 20 (2015) 1–10 5

Fig. 2. The cycle of physical frailty, cognitive frailty and cognitive impairment. The physical impairment caused cognitive frailty is outlined in red arrows, proposed cognitive
frailty components are outlined in red box with pink background and previous cognitive frailty components are outlined in blue dotted line.

frailty-related homeostatic failure. As a consequence, homeostasis
becomes less likely to be sufficient for the maintenance and repair
of the aging body, which in turn becomes vulnerable regarding
stress responses, such that even minor stress events can lead to
the above hormesis process and disproportionate changes in health
(Clegg et al., 2013; Fried et al., 2001, 2009; Varadhan et al., 2008;
Ferrucci et al., 2008; Kalyani et al., 2012; Chaves et al., 2008).
Genetic and environmental stressors may cause dysfunctions
in susceptible neurons of specific brain systems (e.g., medial tem-
poral lobe system and fronto-striatal system) and the decline of
structural (e.g., number of neurons and synapses) and functional
reserves. Finally, heterogeneous brain aging or different neurode-
generative disease occurs (Canevelli et al., 2014). Numerous studies
have revealed that multiple risk factors that cause cognitive impair-
ment are also associated with the development and worsening
of physical frailty in older individuals (Robertson et al., 2013;
Houles et al., 2012; Kelaiditi et al., 2013). The risk factors include
cardiovascular elements (e.g., diabetes, dyslipidemia, hyper-
tension, inflammation and hyperhomocysteinemia), nutrition
(e.g., vitamin D deficiency), hormones (e.g., reduced testosterone,
insulin resistance), lifestyle and mental health issues (Robertson
et al., 2013; Houles et al., 2012; Kelaiditi et al., 2013). There are
intricate connections among physical frailty, changes in cognitive
function and the pathological alterations in dementia. A longitu-
dinal clinical-pathologic study of aging was performed to examine
the relationship between physical frailty in elderly subjects and
common postmortem age-related pathological signs in the brain,
such as cerebral infarcts, the Lewy body pathway and the AD
pathway; the results revealed that physical frailty was related to
the pathology of AD in older persons with and without demen-
tia (Buchman et al., 2008). Another longitudinal clinical-pathologic
study which had an average duration of 6.5 years and had no base-
line of dementia, revealed that physical frailty was associated with a
higher risk of developing non-AD dementia but not AD (Gray et al.,
2013). Furthermore, a recent longitudinal study with an average
duration of 6 years revealed that physical frailty and altered cogni-
tive function were closely related and that brain pathology, which
encompasses AD pathology, macroinfarcts and nigral neuronal loss,
6 Q. Ruan et al. / Ageing Research Reviews 20 (2015) 1–10
displayed a significant correlation with the rate of change in both
physical frailty and cognition. It was therefore postulated that phys-
ical frailty and changes in cognitive function may, in part, share a
common pathological basis (Buchman et al., 2014).
According to our proposed definition, reversible cognitive
impairment of cognitive frailty results from pre-physical or phys-
ical frailty and may lead to an outcome of dementia originating
from AD or other factors (Fig. 2). Thus far, direct evidence
for mechanistically studying cognitive frailty has been lacking,
but epidemiological results have suggested that heart disease,
hypertension, stroke, diabetes, chronic kidney disease and an age-
associated decline in health status were recognized as AD, dementia
or cognitive decline risk factors (Okonkwo et al., 2010; Knopman
and Roberts, 2010; Weiner and Seliger, 2014; Song et al., 2011;
Elwood et al., 2002). A prospective cohort study that had a dura-
tion of 12 years and examined 750 community elderly subjects with
normal cognitive function revealed that physical frailty was closely
associated with the risk of the occurrence of MCI (Boyle et al., 2010).
Likewise, another prospective cohort study which had a duration
of four years and examined 2737 elderly individuals with normal
cognition, also showed that physical frailty was associated with a
faster rate of cognitive decline (Auyeung et al., 2011). Until now,
the mechanism of physical and/or pre-physical frailty that causes
cognitive decline is unknown. An alternative two-hit vascular
hypothesis of AD may be one of the mechanisms of cognitive decline
by physical causes (Sagare et al., 2012; Zlokovic, 2011). Accord-
ing to the hypothesis, vascular risk factors and cerebrovascular
disorder lead to brain oligemia and hypoxia and/or blood-brain
barrier (BBB) dysfunction, which reduce amyloid ␤-peptide (A␤)
vascular clearance across the BBB and increase A␤-production from
A␤-precursor protein, casing A␤-accumulation and tau-related
pathology in brain.
5. The proposed tools to measure reversible cognitive
frailty
Based on the mechanisms of frailty, including those of phe-
notypic, defect accumulation, the aggregation of multifunctional
domains and multidimensions, various frailty-screening tech-
niques have been indicated (de Vries et al., 2011; Bouillon et al.,
2013; Sternberg et al., 2011). Among these, Fried’s phenotypic
physiology-based screening is being preferentially used for frailty
research (Fried et al., 2001), whereas scales for frailty resulting from
defect accumulation are more suitable for health management,
such as predicting whether an elderly individual requires hospital-
ization (Rockwood and Mitnitski, 2007). In addition, those clinical
screening instruments for rapidly examining cognitive impairment
in populations with physical frailty and cognitive frailty, such as
the Simple “FRAIL” Questionnaire Screening Tool and the Rapid
Cognitive Screen (RCS), can meet the daily examination require-
ments of clinicians in identifying subjects at risk (Moeley et al.,
2013; Malmstrom and Morley, 2013). A broad consensus has been
reached for the screening of pre-physical or physical frailty subjects
for cognitive frailty, whereas the screening of cognitive function
in reversible cognitive frailty is absent. We suggest the use of pre-
MCI SCD research criteria with minor modifications, in combination
with suggested SCD features as a preliminary screening tool for
cognitive function, including the following: (1) a self-experienced
persistent decline in cognitive capacity compared with a previously
normal status and unrelated to an acute event; (2) normal age-,
gender- and education-adjusted performance on standardized cog-
nitive tests that are used to classify MCI or prodromal AD; and 1
and 2 must both be met. The exclusion criteria include the follow-
ing: (1) MCI, prodromal AD or dementia and (2) conditions that
can be explained by a psychiatric disorder (reach the threshold of
depression or anxiety), neurologic disease (apart from AD) (Jessen
et al., 2014).
To identify individuals with reversible cognitive impairment
and in an absence of SCD, implementation of a personal secondary
intervention to the pre-MCI SCD caused by physical factors in
individuals with cognitive frailty, having one screening tool to dif-
ferentiate whether a patient with pre-MCI SCD is pre-clinical AD
or another neurodegenerative disease in the subclinical stages is
indispensable. Preclinical AD SCD research criteria, in combina-
tion with biomarkers of preclinical AD, may be a useful screening
tool (Jessen et al., 2014; Sperling et al., 2013). A preliminary
questionnaire screening tool includes the following critical prop-
erties: (1) a subjective decline in memory, rather than in the
other domains of cognition; (2) an onset within the last five
years; and (3) an age at onset of SCD ≥ 60 years. Biomarkers of
preclinical AD include the following: (i) markers of amyloid ␤-
accumulation, such as the level of amyloid ␤42 in cerebrospinal
fluid, and positron emission tomography (PET) amyloid imaging;
(ii) markers of neurodegeneration or neuronal injury, including the
level of tau and phosphorylated tau protein in cerebrospinal fluid;
18 F-fluorodeoxyglucose PET functional imaging or functional mag-
netic resonance imaging (MRI); and nerve degeneration or damage,
such as that revealed by the MRI-based detection of hippocampus
atrophy or cortical thinning. Based on various combinations of amy-
loid ␤-aggregation, nerve degeneration and the subtle reduction of
cognitive function, pre-clinical AD can be divided into four stages
(Sperling et al., 2013). In addition, homozygous ApoE ε4 is a useful
biomarker for late onset familial and sporadic AD patients. In the
absence of results in “classical” cognitive tests, we have to consider
the association of self-report measures with existing biomarkers.
Because of the heterogeneous features of SCD in preclinical AD,
the questionnaire preliminary screening tool does not compre-
hensively define the specific characteristics of SCD in preclinical
AD in individuals of cognitive frailty. According to current knowl-
edge, when all of the self-report measures, markers of amyloid
␤-accumulation and markers of neurodegeneration or neuronal
injury are positive, the subject may belong to stage 2 or 3 of the
proposed staging of preclinical AD by the US National Institute on
Aging (Sperling et al., 2013). When self-report measures and only
markers of amyloid ␤-accumulation are positive, the subject is in
stage 1 of the proposed staging of preclinical AD. Although amyloid
␤-accumulation is currently the first biomarker to indicate AD and
has a greater specificity compared with markers of neurodegen-
eration or neuronal injury, it also may be positive in individuals
who have dementia with Lewy bodies and/or cerebral amyloid
angiopathy. When self-report measures and only markers of neu-
rodegeneration or neuronal injury are positive, the subject may
have suspected non-Alzheimer pathology, including normal aging
and other age-related neurodegenerative diseases. The biomarker
homozygous ApoE ε4 is helpful for the differentiation of diagnosis.
When only self-report measures are positive, the subject is at stage
0 of the proposed staging of preclinical AD. Even if the individual
probably experiences early AD processes that are undetectable with
current biomarkers, the subject should be considered as a normal
individual after excluding psychiatric disorders. If only biomarkers
are positive without self-report measures, the differentiation of the
diagnosis of preclinical AD from other neurodegenerative diseases
is according to the proposed staging of preclinical AD by the US
National Institute on Aging (Sperling et al., 2013).
6. The prevention of cognitive frailty
Preventive intervention is required for elderly subjects in a pre-
physically frail state to reduce the risk of developing physical frailty
syndromes (Abellan van Kan et al., 2008; Lang et al., 2009). In
 Q. Ruan et al. / Ageing Research Reviews 20 (2015) 1–10
addition, secondary interventions should be provided for elderly
subjects with physical frailty syndromes that are in a reversible
state to thereby avoid a reduction in physical functions (Abellan van
Kan et al., 2008). SCD is an effective target for cognitive impairment
intervention (Canevelli et al., 2013; Sperling et al., 2011). Elderly
individuals with cognitive frailty comprise those with pre-physical
or physical frailty combined with pre-MCI SCD and/or positive fluid
and imaging biomarkers of amyloid-␤ accumulation and neurode-
generation. In comparison with pre-physical and physical frailty
syndromes, the prevention of cognitive frailty requires particu-
lar treatments (Fig. 1). For the elderly subjects with reversible
cognitive frailty, primary preventive intervention includes the pro-
motion of physical activities, cognitive stimulation, exercise and a
healthy diet (e.g., a Mediterranean diet, the cessation of smoking,
promoting emotional recovery, engaging in an active and socially
integrated lifestyle, an ideal amount of daily sleep, the mainte-
nance of a proper body weight and metabolic control (including
the control of dyslipidemia, diabetes and blood pressure)), as these
measures boost patients’ ability to fight the disease (Sternberg
et al., 2011; Desai et al., 2010). At this stage, secondary preven-
tions for cognitive imapirment such as preclinical AD0 and physical
frailty are suggested. For the elderly subjects with potential cogni-
tive frailty, secondary prevention is required, which comprises a
geriatric assessment determining the cause of cognitive frailty and
an evidence-based, medicinal, individualized multimodal interven-
tion (Fig. 1). Other measures, such as drug treatment for chronic
diseases, fall prevention, exercise and nutrition support, which tar-
get physical, nutritional, cognitive and psychological domains, may
delay the progression and secondary occurrence of cognitive frailty
related adverse outcomes (Sternberg et al., 2011; Desai et al., 2010;
Kelaiditi et al., 2013; Moeley et al., 2013). Lastly, for the elderly
subjects with irreversible cognitive impairment caused by physical
factors that may lead to adverse health-related outcomes, such as
disability or death, a comprehensive geriatric assessment is always
required for intervention at this stage (Fig. 1). In other words, a
multimodal intervention with the main goal of rehabilitation and
sustaining the quality of life is a suitable choice for these patients.
Many studies have shown that exercise can improve the mobil-
ity and functional ability of frail elderly individuals (de Vries et al.,
2012; Theou et al., 2011; Clegg et al., 2012). The positive influence
of exercise on frailty is partially realized by reducing the systemic,
chronic inflammation in the body (Robertson et al., 2013). Physical
activity can counteract sarcopenia, a major cause of physical frailty,
and cognitive decline (Landi et al., 2010). For example, aerobic
exercise and strength training for 12 weeks resulted in improved
scores in functional capacity, cognition and quality of life (Langlois
et al., 2013). Protein nutritional supplements may act synergisti-
cally with resistance exercise in elderly persons to increase muscle
mass, reduce complications, improve grip strength and produce
weight gain (Tieland et al., 2012a,b; Malafarina et al., 2013; Cawood
et al., 2012). However, one randomized controlled trial that inves-
tigated the effects of exercise and nutritional supplementation in
very elderly frail individuals in a long-term care situation indi-
cated that these treatments had no effect on muscle strength, gait
speed, stair climbing or physical activity (Fiatarone et al., 1994).
Mouse experiments revealed that genetic and/or dietary interven-
tions that promote longevity are protective regarding aging-related
physical frailty (Arum et al., 2014). In addition, several drugs have
been used in intervention studies of frailty, a 3-year follow-up
study in which an angiotensin-converting enzyme (ACE) inhibitor
was used to treat the non-frail at a baseline level in women aged
65–79 years old (N = 27,378); the results revealed that the inci-
dence of frailty was similar in ACE inhibitor users and nonusers
(Gray et al., 2009). It was also reported that testosterone improved
muscle strength but caused side effects in the cardiovascular and
respiratory systems (Basaria et al., 2010). In contrast, IGF 1 did not
7
seem to improve muscle strength or bone density in healthy elderly
women (Friedlander et al., 2001). Moreover, low levels of 25(OH)
D were strongly associated with the prevalence and incidence of
frailty, and moderately elevated levels of C-reactive protein (CRP)
might play a role in the incidence of frailty (Puts et al., 2005b). How-
ever, a series of studies indicated that low levels of 25(OH) D were
associated with the prevalence of frailty in both elderly women
and men and that the level could predict a greater risk of frailty in
elderly women, but not in elderly men (Ensrud et al., 2010, 2011).
Severe vitamin D deficiency was also reported to be associated with
advanced-stage dementia in geriatric inpatients (Annweiler et al.,
2011). Although there is no direct evidence supporting the idea
that a large-scale intervention with vitamin D can prevent or treat
frailty, a meta-analysis demonstrated that the combined treatment
with vitamin D and calcium, but not vitamin D alone, reduced mor-
tality in the elderly subjects (Rejnmark et al., 2012). Sarcopenia is a
common cause of frailty. Young plasma and GDF11 can rejuvenate
aged organ and tissues of the aging mouse, increase physical per-
formance, such as cognitive function and muscular performance
(Villeda et al., 2014; Sinha et al., 2014). GDF11 or oxytocin can acti-
vate adult muscle stem cell, improving muscle regeneration and
performance (Sinha et al., 2014; Elabd et al., 2014). These systemic
factors may potentially contribute to the treatment of cognitive
frailty.
7. Conclusion
Based on the progress of research involving studies of cognitive
impairment and frailty, we herein refine the definition of cognitive
frailty. Consequently, by referring to the level of cognitive impair-
ment caused by pre-physical or physical frailty, we may determine
whether primary prevention or secondary prevention is indicated.
This definition suggests that self-report measures with biomarkers
be used to facilitate the diagnosis (e.g., different combinations of
amyloid-␤ accumulation, neurodegeneration and subtle cognitive
decline) and to further determine whether the SCD is a component
of pre-clinical SCD; this information can then be used for guiding
clinical intervention. However, this revised clinical screening crite-
rion of cognitive frailty still requires a large cohort of elderly to test
the predictive effectiveness of a poor prognosis. Moreover, more
research is also required to determine the physical causes of SCD
from a physiological perspective.
Conflict of interest statement
None declared.
Acknowledgements
This work was supported by grants from the Shanghai Key Lab-
oratory of Clinical Geriatric Medicine Subject Construction (No.
13dz2260700) and Shanghai Hospital Development Center Grant
(No. SHDC12014221).
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