Ageing Research Reviews 12 (2013) 840851

Contents lists available at ScienceDirect

Ageing Research Reviews

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

Review

Frailty and cognitive impairmentA review of the evidence

and causal mechanisms
Deirdre A. Robertson a, , George M. Savva a,b , Rose Anne Kenny a
a
The Irish Longitudinal Study on Ageing, Department of Medical Gerontology, Chemistry Extension Building, Trinity College, Dublin, Ireland
b
School of Nursing Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom

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

Article history: Incidence rates of cognitive impairment and dementia are rising with the ageing population. Meanwhile,
Received 11 March 2013 the limited success of current treatments has led to a search for early markers of dementia which could
Received in revised form 14 June 2013 predict future progression or improve quality of life for those already suffering from the disease. One
Accepted 25 June 2013
focus has been on the correlation between physical and cognitive measures with an increasing interest
Available online 4 July 2013
in the association between frailty and cognitive decline. Frailty is an age-related syndrome described as
the decreased ability of an organism to respond to stressors. A number of epidemiological studies have
Keywords:
reported that frailty increases the risk of future cognitive decline and that cognitive impairment increases
Frailty
Cognition the risk of frailty suggesting that cognition and frailty interact within a cycle of decline associated with
Dementia ageing. This paper reviews the evidence for an association between frailty and cognitive impairment and
Cognitive impairment outlines some of the mechanisms that potentially underpin this relationship from brain neuropathology
and hormonal dysregulation to cardiovascular risk and psychological factors.
2013 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
3.1. Evidence for the relationship between frailty and cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
3.2. Cross-sectional studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
3.3. Longitudinal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
3.4. Cognitive function and indicators of frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
3.5. Domains of cognition impaired in frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
4. Mechanisms behind the link . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
4.1. AD pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
4.2. Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 846
4.3. Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
4.4. Chronic inammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
4.5. Cardiovascular risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
4.6. Mental health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
5. Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 848
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 848
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849

Corresponding author at: The Irish Longitudinal Study on Ageing, Chemistry Extension Building, Trinity College, Dublin, Ireland. Tel.: +353 18963058.
E-mail addresses: robertde@tcd.ie (D.A. Robertson), g.savva@uea.ac.uk (G.M. Savva), rkenny@tcd.ie (R.A. Kenny).

1568-1637/$ see front matter 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.arr.2013.06.004

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 D.A. Robertson et al. / Ageing Research Reviews 12 (2013) 840851
1. Introduction
One of the greatest achievements of public health in the twen-
tieth century has been the almost doubling of life expectancy
in the Western world (Oeppen and Vaupel, 2002). Yet this now
ageing population brings new challenges as the prevalence of
little-understood geriatric conditions increases. One of the biggest
challenges facing modern healthcare is the economic and medical
burden of caring for dependent older people limited by physical
and mental impairments. Two of the most common and yet least
understood of these are frailty and cognitive impairment.
Frailty is a reduction in the ability to respond to stressors
and an increased vulnerability to adverse outcomes (Fried et al.,
2001). Although the trajectory of decline varies widely, it is most
commonly characterised by a progression of physiological decline
leading to dependency and disability (Fried et al., 2001; Gill et al.,
2010). Frailty can be preceded by, but also occurs in the absence of
chronic disease (Rockwood et al., 2007b). The highest prevalence
is found in the older population and advanced age is a major risk
factor (Fried et al., 2001). Frailty has signicant implications for
the ability to maintain independent, high quality living and carries
an increased risk of hospital visits, disability, institutionalisation
and death (Heuberger, 2011). There is no consensus on how best
to operationalise or dene frailty but two types of denitions have
emerged as the most commonly used constructs:
1) The Cumulative Burden Index as proposed by Rockwood et al.
(1994; Rockwood and Mitnitski, 2007b): frailty is dened as
an accumulation of health conditions and decits. The index of
decits is not limited to those included in the original model
but can include any domains that full the criteria laid out by
Rockwood and colleagues.
2) The Biological Syndrome Model as proposed by Fried et al.
(2001): a person is deemed to be frail if they present with three
or more of: poor grip strength, slow walking speed, low levels
of physical activity, exhaustion and unintentional weight loss.
A number of variations on these models of frailty have emerged
over the past decade but the underlying constructs remain broadly
similar. The Fried and Rockwood models are moderately correlated
with each other and are associated with the same adverse outcomes
(Rockwood et al., 2007a).
Cognitive impairment is the decline of intellectual functions
such as thinking, remembering, reasoning and planning. It is com-
mon among older people but the effects range from mild forms
of forgetfulness to severe and debilitating dementia. Mild cogni-
tive impairment (MCI) is a term used to dene a state of cognitive
decline that is not accompanied by any signicant functional dis-
ability (Allegri et al., 2008; Petersen and Negash, 2008). It has
a high rate of progression to all types of dementia in which
severe cognitive impairment is accompanied by increasing phys-
ical decline, eventually leading to full physical dependency. The
Medical Research Council Cognitive Function and Ageing Study, a
10 year population-based cohort study of individuals 65 and over
in England and Wales, reported that dementia has a prevalence of
around 10% in the population aged 65 and over, and a prevalence
at death of one in three (Brayne et al., 2006). Up to one quarter of
hospital beds in the UK are in use by people over 65 years old with
dementia and the prevalence is around 50% among those in insti-
tutional care (Lakey, 2009; Matthews and Dening, 2002). Dementia
has an enormous impact on the individual, their families, health-
care systems and wider society, with a direct cost of healthcare
services associated with each person with dementia of $17,700 per
year (Wimo et al., 2007).
Many pathological processes contribute to cognitive impair-
ment, leading to several possible avenues for dementia prevention.
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841
A signicant fraction of dementia in the population is attributable to
neuropathology such as the neocortical neurotic plaques and tan-
gles associated with Alzheimers disease (19%) or cerebrovascular
pathology (21%) but much remains unexplained (Brayne and Davis,
2012; Matthews et al., 2009). Age is consistently reported as the
most important independent risk factor for cognitive impairment
and dementia, and so it is likely that many of the age-associated
processes that lead to frailty in older people are also responsible
for brain ageing and consequent cognitive decline. The benets
of understanding the relationship between cognition and frailty
are twofold: First, the frail are likely to be at high risk of cogni-
tive impairment and vice versa. Second, understanding the link
between frailty and cognition may lead to new interventions for
the prevention and management of both conditions.
The place of cognitive impairment in a denition of frailty has
been widely debated. Frieds model does not include cognitive
function in its denition, while Rockwoods model allows poor
cognition to be included as one of the possible decits. Recent
consensus papers have suggested that an operational denition of
frailty should include components from the domains of nutrition,
mobility, physical activity, strength, endurance, balance, cognition,
senses, mood, coping, social relations and social support although
researchers do not agree on diagnostic procedures to achieve this
denition of frailty (Gobbens et al., 2010; Rodriguez-Manas et al.,
2013). A recent review of frailty measures found that the most com-
monly included components in an operational denition of frailty
were physical function, gait speed and cognition, with cognition
being included in 50% of the denitions (Sternberg et al., 2011). On
the other hand, statistical analyses on these proposed components
of frailty suggest that, while physical activity, mobility, energy,
strength and mood aggregate as one concept, cognition does not
correlate strongly with this and therefore may not be part of the
frailty syndrome (Sourial et al., 2010, 2012). Furthermore, a recent
study of Alzheimers dementia (AD) patients found that 22% had no
indications of frailty (Bilotta et al., 2012a,b). It seems most useful
therefore to treat frailty and cognitive impairment as related but
distinct concepts which frequently co-occur.
A 2011 review described several studies illustrating a link
between frailty in dementia and pre-dementia cognitive states,
highlighting the scarcity of information at that time on the magni-
tude of the association and mechanisms underlying the link (Panza
et al., 2011). Interest in this eld has rapidly developed over the
course of two years. Many epidemiological studies from different
countries have since explored this association and, of particularly
relevance, many have disentangled the broad concepts of frailty and
cognition into their specic components in order to better under-
stand the relationship. Here we update the 2011 review to include
these new studies on the relationship between frailty and cogni-
tive impairment, the possible mechanisms behind this association,
and its signicance with respect to the possibility of future inter-
ventions to interrupt the progression of either frailty or cognitive
decline.
2. Methods
We searched PubMed for papers published before May 2013
we did not specify a lower date limit using combinations of the fol-
lowing keywords: frail, frailty, cognition, dementia and Alzheimers
disease. One thousand three hundred and fourteen abstracts were
reviewed for relevance including those already contained within
the Panza et al., review. We did not apply strict inclusion or exclu-
sion criteria but included all papers which examined cognition and
an operationalised denition of frailty in the ageing population.
We also included papers of interest from the reference lists of the
selected articles. We excluded papers based on frailty in specic
842 D.A. Robertson et al. / Ageing Research Reviews 12 (2013) 840851

patient populations, such as HIV and cancer sufferers, as well as
any study which did not dene their measurement of frailty.
3. Results
3.1. Evidence for the relationship between frailty and cognition
The relationship between cognitive impairment and frailty has
been demonstrated both cross-sectionally and longitudinally by a
number of epidemiological and clinical studies. These are described
in Tables 1 and 2.
3.2. Cross-sectional studies
Several cross-sectional studies have demonstrated higher rates
of cognitive impairment in frail compared to pre-frail or robust
older people. Data from the Three City Study suggests that 22%
of frail participants had cognitive impairment (dened as being
in the lowest quartile of both the Isaacs Set Test and the Mini
Mental State Examination (MMSE)) compared to only 12% and 10%
in the pre-frail and robust populations (vila-Funes et al., 2009).
The relationship between general cognitive function and frailty
has also been consistently demonstrated in cross-sectional studies
which have used both Frieds biological model (vila-Funes et al.,
2009; Jurschik et al., 2012; Macuco et al., 2012; Ni Mhaolain et al.,
2011; Yassuda et al., 2012) and Rockwoods cumulative burden
index (Mitnitski et al., 2011a; Rockwood et al., 2007a) (Table 1).
Frailty and dementia also co-occur. A study of 23,952 home care
recipients found that 40% of participants classied in the frailest
category using Rockwoods frailty index had a diagnosis of demen-
tia compared to 11% of those in the least frail category (Armstrong
et al., 2010). This relationship remained consistent when other
frailty denitions were used. In another study of 313 outpatients
attending a geriatrics clinic in Italy, Bilotta et al. (2012b) found
that 33% of robust participants and 32% of pre-frail participants
had a diagnosis of dementia compared to 45% of frail partici-
pants, although this difference was not statistically signicant.
Conversely, in another study using only 109 patients diagnosed
with dementia, 50% were frail, 28% were pre-frail only and 22%
had no indications of frailty (Bilotta et al., 2012a,b) (Table 1).
3.3. Longitudinal studies
A number of longitudinal studies have suggested that higher
levels of frailty predict cognitive decline (Auyeung et al., 2011;
Mitnitski et al., 2011a,b; Samper-Ternent et al., 2008); and inci-
dent dementia (Avila-Funes et al., 2012; Boyle et al., 2010; Buchman
et al., 2007; Gray et al., 2013; Solfrizzi et al., 2013; Song et al., 2011).

Table 1
Cross-sectional studies showing an association between frailty and cognitive impairment or dementia.

Reference Population characteristics Demographics Measure of frailtya Measure of cognition Findings

vila-Funes et al. (2009)
Three City Study: Population N = 6.030 Fried criteria MMSE and Isaacs Set CI in 22% of frail
based sample of community Age: 74.1 (5.2) Test of verbal uency. population, 12% of pre-frail
dwelling adults aged 65+ from 61.4% female. Cognitive impairment and 10% among robust.
Bordeaux, Dijon and dened as lowest
Montpellier. quartile.

Macuco et al. (2012)/Yassuda Population based sample of N = 384 Fried criteria. The Brief Cognitive CI in 39% of frail
et al. (2012) community dwelling adults Age: 72.3 (5.8) Screening Battery. population, 22% of pre-frail
aged 65+ from low 67.2% female. MMSE and and 16% of robust.
socio-economic area of Brazil. sub-domains.

Jurschik et al. (2012) Sample taken from population N = 628 Fried criteria. Pfeiffers Test for CI in 20% of frail population
based sample of community Age: 81.3(5) Cognitive Function. compared to 5.3% of robust
dwelling adults aged 75+ in 60.3% female. Cognitive impairment population.
Spain. is 3 errors.

Rockwood et al. (2007a,b) CSHA study. Population based N = 716 in long Fried criteria and Modied Mini Mental Fried (r = .58) and
sample of adults in the term care. Rockwoods Frailty State Examination Rockwood (r = .35)
community and in N = 1589 Index. (3MS) models negatively
institutionalised care in community correlated with 3MS
Canada. dwelling.

Armstrong et al. (2010)
Database of 23,952 patients N = 23,952. Frailty index. Reported Diagnosis of Dementia in 40% of frailest
receiving community care in Age: 81.7 (7.4) Dementia. (top 15% of FI) compared to
the home or in long-term care 69.4% female. 11% of least frail (lowest
institutions across Ontario, 60% of FI).
Canada.

Bilotta et al. (2012a)
Participants attending an
outpatient geriatric clinic in
Italy.
N = 313. SOF criteria: Diagnosis of dementia. Dementia in 45% of frail
Age: 81.5 (6.8) participants compared to
71% female. 32% in pre-frail and 33%
robust (not statistically
signicant).

Bilotta et al. (2012b)
Participants attending an N = 109. SOF criteria. MMSE 50% of patients with
outpatient geriatric clinic in Age: 82.8 (7.1) dementia were frail, 28%
Italy who had already been 77% female. were pre-frail and 22%
diagnosed with dementia or were robust. Frail
who were subsequently participants with dementia
diagnosed in the clinic. had signicantly lower
MMSE than robust
participants with
dementia.

Fried criteria: Denition similar to that described in Fried et al., 2000.

SOF criteria: Study of osteoportic fractures criteria: Frailty dened as 2/3 of i) unintentional weight loss> 5%, ii) inability to rise from a chair 5 consecutive times without
using the arms and iii) negative answer to the question do you feel full of energy?
MMSE: Mini-mental state examination; CI: Cognitive impairment

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 Table 2
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Longitudinal studies of the effect of frailty on cognitive decline or dementia incidence.
(a)
Reference
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vila-Funes et al. (2009)
vila-Funes et al. (2012)
Samper-Ternent et al.
(2008)
Mitnitski et al. (2011a)
Mitnitski et al. (2011b)
Drame et al. (2011)
Buchman et al. (2007)
Boyle et al. (2010)
Study population
Three City Study:
Population based sample of
community dwelling adults
aged 65+ from Bordeaux,
Dijon and Montpellier.
Three City Study:
Population based sample of
community dwelling adults
aged 65+ from Bordeaux,
Dijon and Montpellier.
HEPESE study. Population
based sample of
Mexican-American adults
in the community aged
65+.
CSHA study. Population
representative sample of
adults in Canada.
Subset of CSHA study.
Population representative
sample of adults in Canada.
SAFEs study. Participants
aged 75+ admitted to ED in
hospitals around France.
Rush Memory and Ageing
Project. Participants from
residential centres, social
services and church groups
across Chicago.
Rush Memory and Ageing
Project. Participants from
residential centres, social
services and church groups
across Chicago.
Sample characteristics Baseline measure of Follow-up period and Baseline covariates Findings
frailty measure of cognitive accounted for.
change
N = 6030 Fried criteria 4 year incidence of Age; sex; education; Pre-frail vs robust:
Age: 74.1 (5.2) dementia income; smoking; drinker; HR = 1.29 (0.861.93)
61.4% female. number of chronic
diseases; SRH; CES-D, Frail vs robust:
mobility, IADL and ADL HR = 1.14 (0.582.21)
N = 5480. Fried criteria. 7 years incidence of Age, sex, education, Dementia:
61.7% female. dementia (all cardiovascular risk factors, Pre-frail vs robust:
Mean age: 74 (5.2) dementia, AD and VaD) diabetes mellitus, HR = 1.20 (0.961.51)
after 7 year follow up. hypercholesterolemia, Frail vs robust: HR = 1.24
history of coronary disease, (0.942.01)
D.A. Robertson et al. / Ageing Research Reviews 12 (2013) 840851
APOE genotype, ADLs. AD:
Pre-frail vs robust:
HR = 1.19 (0.921.53)
Frail vs robust: HR = 1.23
(0.791.91)
VaD:
Pre-frail vs robust:
HR = 1.74 (0.893.39)
Frail vs robust: HR = 2.73
(1.057.13)
N = 1370. Fried criteria. Ten year decline in Age, sex, marital status, Frailty but not pre-frailty
Total sample age and MMSE. education, stroke, heart associated with cognitive
gender not given. attack, hypertension, decline.
diabetes, high depressive
symptoms, arthritis, visual
impairment.
N = 9266. Rockwoods Frailty Five year change in Cognition, age, sex, Frailty associated with
Age: 75.8 (7.1) Index. errors on 3MS grouped education cognitive change in men
60.2% women. into categories of 3 and women
N = 2305. 1. Fried criteria. Five year change in Cognition, age, sex, All measures associated
Age: 83.1 (6.9). 2. Frailty Index. errors on 3MS grouped education. with cognitive decline
62.1% female. 3.Clinical Frailty Scale into categories of 3
N = 1306. Four different indices 1 Year Rapid Cognitive None Exact tests showed no
Age: 85 (5.9) including Rockwood Decline (RCD): loss of association between frailty
64.7% female. index. 3 points on MMSE and RCD.
Baseline MMSE: 16 +- 5
N = 823. Z-score based on grip 7 years incidence of AD Age, sex, education HR = 1.94 (1.312.87)*
Age: 80.4 (6.9) strength, timed walk, (adjusting for additional
74.6% female. BMI and exhaustion. vascular factors or disease
did not affect estimate)
N = 750. Z-score based on grip 12 years incidence of Age, sex, education HR = 1.6 (1.32.1)*
Age: 79 (7.1) strength, timed walk, MCI depression, disability,
76.4% female. BMI and exhaustion. vascular risk factors, and
vascular diseases.
843
 844
Gray et al. (2013) ACT study. Population N = 2619 Fried criteria. 16 year incidence of Age, sex, education, race, Frail vs robust:
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based sample of Age: 76.8 (5.9) dementia, classied as BMI, depression, Dem: HR = 1.20 (.851.69).
individuals aged 65+ from 60.1% female. possible/probable AD anti-depressants, AD: HR = 1.08 (.741.57)
a health maintenance or non-AD. cardiovascular health, non-AD: HR = 2.57
organisation in Seattle. smoking, cognition (1.086.11)

Song et al. (2011) CSHA study. Population N = 5909. Frailty Index of 5 year incidence of AD Age, sex, education, Non-traditional risk factors
based sample of adults in Age and sex not given non-traditional risk or other dementia. cognition combine to increase risk of
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the community and in factors for dementia. dementia and AD.

institutionalised care in
Canada.

Solfrizzi et al. (2012)
ILSA study. Randomly
selected, population based
sample of free-living or
institutionalised
participants aged 65 to 84
years.
N = 2581. Fried criteria. 3.5 year incidence of Age, sex, education, AD: HR = 0.62 (0.201.89)
45% female. AD, VaD and other smoking, IADL, MMSE, VaD: HR = 2.68 (1.167.17)
Age 73.1 (5.6) dementia. co-morbidity and serum Other dem: HR = 2.69
albumin (0.5114.13)

D.A. Robertson et al. / Ageing Research Reviews 12 (2013) 840851

Auyeung et al. (2011)
Community dwelling,
cognitively normal people
aged 65+ living in Hong
Kong.
N = 2737. BMI, grip strength, Four year change in Age, education and MMSE. Only grip strength
Age: chair stand, step MMSE. predicted lower MMSE at
Male: 71.6(4.58). length, slowed walk, follow up in women.
Female: 71.5 (4.85). composite score on Underweight, grip strength
44.7% female. neuromuscular tests. and chair stand led to
cognitive decline in men.

(b)

Reference Study population Sample characteristics Measure of cognition Follow-up period and Baseline covariates accounted for Findings
measure of frailty

Aranda et al. (2007) HEPESE study. N = 963. MMSE Two year change in Age, gender, education, language, nances, Incident frailty linked
Representative sample Age and sex not given. Fried criteria with the private insurance, medical conditions, being to baseline cognition
of Mexican-American exclusion of physical underweight and ADLs, positive affect, living
adults in the activity. alone, emotional support, neighbourhood.
community aged 65+.

Raji et al. (2010) HEPESE study. N = 942. MMSE dichotomised Ten year change in Age, gender, marital status, education, medical Incident frailty linked
Population based Total sample age and into cognitive Fried criteria with the conditions to baseline cognition
sample of gender not given. impairment exclusion of physical
Mexican-American (MMSE < 21) or none. activity.
adults in the
community aged 65+.

Doba et al. (2012) Sample taken from N = 407. Minimum Data Set Five year change in Age, sociodemographics, frequency of going Subjective cognitive
larger longitudinal Age: 78(4). cognitive performance Canadian Study for out, anorexia, insomnia, exercise tolerance, changes at baseline
study of community 54.79% female. scale. Self-reported Health and Ageing mood, fatigue, history of falls, vision and were signicantly
dwelling participants cognitive change. Clinical hearing, height, weight, BMI, body fat ratio, associated with
in Japan aged 70+. Frailty Scale grip strength, timed walk, resting metabolic development of frailty
(CSHA-CFS), ratio, bone mineral density, blood pressure, at follow up. There was
heart rate, brachial-ankle pulse wave velocity, no signicant
blood count, creatinine, blood urea nitrogen, association between
serum electrolytes, cholesterol, protein MDS and development
albumin, haemoglobin, cortisol, luteinizing of frailty at follow up.
hormone, deyhdropiandrosterone, C-reactive
protein, interleukin-6, lymphocyte count.

AD: Alzheimers disease; VaD: Vascular dementia; MMSE: Mini-mental state examination; 3MS: Modied mini-mental state examination; Dem: dementia; BMI: Body mass index; ADL: Activities of daily living; IADL: Instrumental
activities of daily living; HR: Hazard ratio.
*
HR for one unit increase in frailty Z-score.
 D.A. Robertson et al. / Ageing Research Reviews 12 (2013) 840851
This relationship has been observed in samples both of commu-
nity living older people (Avila-Funes et al., 2012; Gray et al., 2013;
Samper-Ternent et al., 2008; Solfrizzi et al., 2013; Wang et al., 2006)
and among samples also including participants in long term care
facilities (Mitnitski et al., 2011a,b; Song et al., 2011). The recipro-
cal relationship, that cognitive impairment indicates future frailty,
has also been reported in three epidemiological studies based on
samples of community dwelling older adults (Aranda et al., 2011;
Doba et al., 2012; Raji et al., 2010) (see Table 2).
Some studies, however, have failed to nd this relationship, or
have only seen associations with frailty and specic dementia sub-
types. The Three City Study found that the excess risk of incident
dementia associated with baseline frailty was explained by adjus-
ting for baseline social and health conditions (vila-Funes et al.,
2009). In a later analysis of the Three City Study, an effect of frailty
on incident vascular dementia but not with AD or other dementias
was found (Avila-Funes et al., 2012). Data from the Italian Longitu-
dinal Ageing Study (Solfrizzi et al., 2013) and the population-based
Adult Changes in Thought study (Gray et al., 2013) also suggest
an association between frailty and incident non-AD dementia, but
not with AD. In a study of 1306 French older adults admitted to
emergency departments, frailty measured at admission was not
associated with cognitive decline over the subsequent year irre-
spective of the frailty denition employed (Drame et al., 2011).
Existing cognitive impairment is linked to frailty and is a strong
risk factor for further cognitive decline and dementia incidence, and
so absent or inadequate control for baseline cognitive status may
lead to spurious associations being observed. Several studies do nd
a residual effect of frailty on cognitive decline and incident demen-
tia after adjusting for baseline cognition (Auyeung et al., 2011; Gray
et al., 2013; Mitnitski et al., 2011a,b; Solfrizzi et al., 2013; Song et al.,
2011), however two do not (vila-Funes et al., 2009; Drame et al.,
2011). Multiple regression including baseline cognition, multi-level
models that account for the covariance between baseline cogni-
tion and baseline frailty and models based on transitions from
one cognitive state to another have all been used to account for
the potentially confounding effects of baseline cognitive function,
however controlling for cognition is known to be difcult due to
within person variation in day-to-day testing and it is possible that
observed effects may yet represent a residual confounding due to
these measurement errors (Dugravot et al., 2009).
3.4. Cognitive function and indicators of frailty
Some indicators of frailty have been shown better predict cog-
nitive decline than others. Boyle et al. (2010) found that timed walk
and grip strength were the signicant predictors of subsequent
diagnosis of Mild Cognitive Impairment (MCI) but unintentional
weight loss and exhaustion were not. Auyeung et al. (2011) showed
that the frailty measures predicting cognitive decline varied by sex,
such that after adjustment for age, years of education and baseline
MMSE score only grip strength predicted lower MMSE scores in
women while weight loss, grip strength and chair stands predicted
lower MMSE scores in men. Low gait speed was the only indicator
of frailty signicantly associated with incident vascular dementia
among ACT study participants (Gray et al., 2013), although other
indicators may have contributed. Strong links have been found
between cognition and poor grip or muscle strength (Alfaro-Acha
et al., 2006; Boyle et al., 2009; Shechtman et al., 2004; Yassuda et al.,
2012), slow gait speed (Abellan van Kan et al., 2009; Buracchio et al.,
2010; Camicioli et al., 1998; Ijmker and Lamoth, 2012; Yassuda
et al., 2012), weight loss (Buchman et al., 2005; Stewart et al., 2005;
Wirth et al., 2011) and low levels of physical activity (Buchman
et al., 2012; Landi et al., 2010). These relationships fall outside
the scope of the current review but have been reviewed by other
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845
authors (Clouston et al., 2013; Landi et al., 2010; Abellan van Kan
et al., 2009).
3.5. Domains of cognition impaired in frailty
As well as considering the effect of frailty on dementia subtypes,
a number of recent papers have also begun to explore the effect of
frailty on specic cognitive domains, however only two of these
have been large scale epidemiological studies. The Rush Memory
and Aging Study found that frailty was signicantly associated with
global cognition and perceptual speed but not with episodic mem-
ory, semantic memory, working memory or visuospatial ability
(Boyle et al., 2010). Frailty was, however, associated with a more
rapid rate of decline in all domains. The Brazilian FIBRA study found
that frail participants were more signicantly impaired on the
MMSE, orientation, commands, immediate memory, verbal uency
and the clock drawing test, but not on delayed memory (Macuco
et al., 2012; Yassuda et al., 2012). In a smaller sample of 83 commu-
nity living older people, executive functions and processing speed
were signicantly associated with frailty while global cognition,
episodic memory, working memory or verbal abstract reasoning
were not (Langlois et al., 2012). Among 61 inpatients on a geriatric
rehabilitation ward, higher scores on a cumulative burden of illness
scale were associated, after adjustment for age and depression, with
executive function, reasoning, dual-attentional processing, verbal
uency, and processing speed, but again not with memory (Patrick
et al., 2002). Poorer sustained attention has also been linked to
frailty in community dwelling older people (OHalloran et al., 2011).
The pattern emerging from these studies suggests that gait
speed or grip strength are the components of frailty most strongly
associated with cognitive function while the executive function and
attention domains of cognition are consistently related to frailty.
Gait speed is particularly affected by impairment in executive func-
tions (see also Beauchet et al., 2012; Ijmker and Lamoth, 2012;
Montero-Odasso et al., 2012) and this may be one explanation for
the link between frailty and cognition. Patrick et al. (2002) and
Langlois et al. (2012) also suggested that their ndings may be
partly explained by cardiovascular factors as both frailty and execu-
tive function impairment have been associated with cardiovascular
disease and risk factors (Langlois et al., 2012; Patrick et al., 2002).
Memory does not appear to be strongly related to frailty (Patrick
et al., 2002; Yassuda et al., 2012) however, in most of these studies
frail participants did have poorer memory scores that fell just short
of the criteria for statistical signicance (Boyle et al., 2010; Langlois
et al., 2012; Macuco et al., 2012; Yassuda et al., 2012) (Table 3).
4. Mechanisms behind the link
Although there is now signicant epidemiological evidence link-
ing elements of frailty and cognitive decline, little work has directly
explored mechanisms underlying this link. A number of papers out-
lined below have suggested mediators or possible pathways but
there is a lack of experimental evidence to support these sugges-
tions.
4.1. AD pathology
It is possible that indicators of frailty are directly affected by
neuropathology that also leads to cognitive impairment. Using
brain autopsies from participants of the Rush Study, Buchman
and colleagues compared level of frailty (as dened by a com-
posite measure of grip strength, timed walk, body composition,
and fatigue) approximately 6 months before death to levels of AD
pathology (specically neurobrillary tangles and plaques), Lewy
Bodies and cerebral infarcts at autopsy (Buchman et al., 2008). Only
AD pathology was associated with increased level of frailty and
846 D.A. Robertson et al. / Ageing Research Reviews 12 (2013) 840851

Table 3
Specic aspects of cognition which have been found to be impaired in frailty.

Reference Study population Demographics Measure of frailty Measure of cognition Results

Langlois et al. (2012)
Community dwelling
adults aged between
69 and 81 recruited
through advertisement
in newspapers and
locally.
N = 83.
Total sample age and
gender not given.
Frail if 2/3 of: MMSE, verbal abstract Frailty liked to
-Fried frailty reasoning, episodic impaired executive
-Rockwood frailty memory, working function and
-Low score on Modied memory, speed of processing speed. No
Physical Performance processing and effect on working
Test. executive function. memory, episodic
memory or abstract
verbal reasoning.

Patrick et al. (2010)
Sample of patients
admitted consecutively
to geriatric
rehabilitation inpatient
services in Ottawa,
Ontario.
N = 61. Cumulative Illness
Age: 82.7 (5.8) Rating Scale (CIRS):
72% female. Physician rated
severity of illness in 13
potential categories.
Visuospatial ability, CIRS cross-sectionally
verbal uency, abstract linked to poorer
reasoning, social reasoning,
comprehension, dual-attentional
sustained attention, processing, verbal
episodic memory, uency and speed of
verbal learning & processing., but not
executive function. memory after adjusting
for age and depressive
symptoms.

OHalloran et al. (2011) Cross-sectional
convenient sample of
community dwelling
participants over 60.
N = 384.
Total sample age and
gender not given.
Fried criteria.
Sustained Attention More errors and
Response Time (SART) greater variability in
Task. performance speed in
frail compared to
robust participants.

Macuco et al. Population based
(2012)/Yassuda et al. sample of community
(2012) dwelling adults aged
65+ from low
socio-economic area of
Brazil.
N = 384 Fried criteria. The Brief Cognitive Frailty associated with
Age: 72.3 (5.8) Screening Battery time orientation,
67.19% female. measuring delayed commands and
memory, verbal immediate memory,
uency and the Clock and all BCSG domains.
Drawing Tests. MMSE Adjustment for
and sub-domains. sociodemographic
factors only verbal
uency and clock
drawing remained
linked to frailty.

Delayed memory not

linked to frailty.

Boyle et al. (2010)
Rush Memory and
Ageing Project.
Participants from
residential centres,
social services and
church groups across
Chicago.
N = 761. Composite measure of MMSE, composite Frailty at baseline
Age: 79 (7.1) grip strength, timed cognitive score of associated with
76.4% female walk, BMI and global cognition in baseline perceptual
exhaustion. addition to composite speed but not episodic
score of episodic memory, semantic
memory, working memory, working
memory, perceptual memory or
speed and visuospatial visuospatial ability.
ability. Frailty associated with
more rapid decline in
all domains.

this remained signicant in persons with and without dementia.
Consistent with this nding, the Religious Orders Study found that
substantia nigra neurobrillary tangles, but not cerebral infarcts,
were linked to gait impairments regardless of whether or not the
participants had a diagnosis of dementia (Schneider et al., 2006).
There is a discrepancy between these results and those from the
neuropsychological studies outlined above, which suggest that
frailty is more strongly linked to non-AD dementia and to non-
amnestic cognitive domains. Indeed Panza et al. suggested that as
the Religious Orders Study and Rush Memory and Ageing study
did not directly assess motor brain regions, they may be under-
estimating the effects of cerebral infarcts in frailty, particularly as
damage to the motor cortices in dementia has previously been asso-
ciated with components of frailty (Panza et al., 2011). A further
study from the Religious Orders Study reported that participants
with MCI who had a history of stroke were signicantly impaired
on gait speed compared to participants with no cognitive impair-
ment while those with MCI but no history of stroke were not
impaired on motor measures (Aggarwal et al., 2006). Low gait speed
did, however, signicantly increase the risk of developing AD after
accounting for stroke. There is thus a small amount of research
suggesting that different components of Frieds denition of frailty
may be related to changes in the brain including AD pathology and
cerebral infarcts. However we found only one study which included
a full measure of frailty as opposed to individual components of
Frieds denition.
4.2. Hormones
Two recent reviews have also suggested that reduced testos-
terone and other androgen hormones may be involved in the
development of frailty and cognitive decline (Maggio et al., 2012;
Muller et al., 2003). Testosterone is thought to have protective
effects on cognition through its promotion of synaptic plasticity
in the hippocampus and its regulation of the accumulation of amy-
loid beta protein (Maggio et al., 2012). Furthermore, age related
depletion of testosterone is thought to be associated with declin-
ing muscle mass, an important factor in the development of frailty
(Muller et al., 2003). It is thus possible that reduced testosterone
may be a mediator in this relationship or common underlying

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 D.A. Robertson et al. / Ageing Research Reviews 12 (2013) 840851
factor to both frailty and cognitive decline. Insulin is another pro-
posed mediator in the relationship between frailty and cognition as
insulin resistance (thought to be age-associated decline of insulin
sensitivity) has been found to be associated both with increased risk
of developing frailty, even after adjustment for confounders such as
chronic illness, and also with poor cognitive function (Abbatecola
et al., 2007).
4.3. Nutrition
Nutrition may also play a role in the link between cognition
and frailty due to both the biological and the behavioural effects of
diet Sarcopenia is thought to be strongly associated with develop-
ment of frailty and cognitive impairment. Perhaps due to oxidative
stress (Mulero et al., 2011; Nourhashmi et al., 2002). Adherence
to a Mediterranean diet, high in antioxidants, has been linked to
both lower frailty and better cognitive function (Mulero et al., 2011;
Talegawkar et al., 2012). Findings from the EPIDOS cohort, how-
ever, found that poor cognitive function was not associated with
any of 6 different denitions of sarcopenia but was independently
associated with poor grip strength and slow walking speed suggest-
ing an association caused by factors other than muscle weakness
due to sarcopenia (Abellan van Kan et al., 2013). Nutrition may
also be related to frailty through behavioural changes such as not
remembering or being willing to eat or inability to plan a healthy
diet. Wirth et al. (2011) found that female gender and cognitive
impairment were risk factors for unintentional loss of fat mass
and this, they suggested, was most likely due to behavioural fac-
tors such as forgetting to eat, being easily distracted at mealtimes,
increasing apathy and inability to plan for and maintain a healthy
diet.
4.4. Chronic inammation
Chronic inammation has also been linked to both frailty and
cognitive function (Canon and Crimmins, 2011; Mulero et al., 2011;
Nourhashmi et al., 2002; Panza et al., 2011). Metabolic changes,
chronic illness, lifestyle factors, stress and other factors can ini-
tiate an inammatory response. Proinammatory cytokines such
as interleukin-6 (IL-6) and tumour necrosis factor (TNF)- are
released and coordinate a local inammatory response at the site
of injury as well as starting a systemic response which involves the
release of acute phase proteins such as C-reactive protein (CRP). IL-
6 and TNF- have previously been associated with frailty (Mulero
et al., 2011). Usually the inammatory processes are terminated by
anti-inammatory factors but if the body is under continuous by
subclinical infections, the inammatory state will become chronic
(Mulero et al., 2011). Chronic inammation as a process of ageing
(immunosenescence or inammaging) is a rapidly evolving area
and has been found to be associated with poor physical perfor-
mance and weakened muscle mass. A recent review also suggested
that as the central nervous system and the immune system are
in constant communication, inammation in one area of the body
may be expected to lead to inammation in the brain (Rosano et al.,
2012). If, for example, there is an inammatory response in cerebro-
vascular areas this may trigger cells in the bloodbrain barrier to
also release inammatory cytokines into the brain. Inammatory
cytokines such as IL-6 are thought to interrupt adult neurogen-
esis and as IL-6 receptors are located in the hippocampus and
pre-frontal cortex this heightened inammatory state could have
serious consequences for cognitive function, in particular for mem-
ory and executive functions (Rosano et al., 2012). We found one
study which directly tested the relationship between frailty, cog-
nition and inammation. Canon and Crimmins (2011) found that
levels of circulating C-reactive protein mediated the relationship
between muscle strength and poor cognitive function, albeit only
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847
in women. Chronic inammation is also known to be implicated in
disruption to brain mechanisms, hormonal dysregulation, oxida-
tive stress, cardiovascular disease and social vulnerability, all of
which may be implicated in the relationship between frailty and
cognition (Ble et al., 2006; Dugan et al., 2009; Mulero et al., 2011;
Muller et al., 2003; Rosano et al., 2012).
4.5. Cardiovascular risk
Cardiovascular risk may be another factor in the link between
frailty and cognition. Frailty has previously been found to be associ-
ated with higher rates of cardiovascular disease (Alalo et al., 2009)
and it is known that vascular risk factors play a key role in the devel-
opment of cognitive decline and dementia (De La Torre, 2010). In
addition to inammation, cardiovascular factors may contribute
to frailty through impaired muscle function (Strandberg et al.,
2013). Specically, small-vessel disease and low-grade inamma-
tion would impair blood ow to skeletal muscles thus causing
sarcopenia and muscle weakness. Two epidemiological studies also
found that participants who were frail at baseline had a signicantly
increased risk of developing vascular dementia, over other types of
dementia, compared to non-frail participants (Avila-Funes et al.,
2012; Solfrizzi et al., 2013). This may be particularly interesting in
light of the cognitive ndings outlined above as executive function
is thought to be more signicantly impaired by vascular disease
than memory (Moorhouse and Rockwood, 2008).
4.6. Mental health
Mood disorders such as depression have been found to be both
a risk factor for and a consequence of frailty (Mezuk et al., 2012;
Paulson and Lichtenberg, 2012). Depression is also known to affect
cognitive function (for a recent meta-analysis see Lee et al., 2011).
This suggests that one mechanism underlying the link between
frailty and cognition may be due to psychological factors such
as mood. Once again the vascular link may be important as the
Health and Retirement Survey recently found that participants with
vascular depression at baseline were signicantly more likely to
develop frailty (Paulson and Lichtenberg, 2012). Fifty ve per cent
of participants with vascular depression became frail within four
years compared to 35% of participants with a high cerebrovascular
burden alone and 25% of participants with neither. This may sug-
gest that the interaction between the vascular burden and mood
effects of depression is an important consideration in understand-
ing frailty.
Personality and perceptions of ageing may also play a role
through their effects on mental, physical and social activity. In one
review on the frailty syndrome Lang et al. (2009) suggested that
frailty could be described as a cycle whereby age-related changes to
bone density and muscle cause an increase in the effort required to
be physically active. As the perception of exercise effort increases,
older individuals start to avoid exercise leading to a cycle of increas-
ing sarcopenia and declining physical activity. We found one paper
which tested this theory; young participants, who at rst became
fatigued and weaker when asked to rapidly perform a grip strength
test with their dominant hand, could later overcome fatigue when
a mirror box superimposed a picture of the non-dominant hand
where their dominant hand was gripping. This suggests that the
weakness and fatigue were not a cause of muscle fatigue per se but
of perceived fatigue and weakness (Tanaka et al., 2011). Physical
exercise in later life, even less vigorous activities such as walk-
ing, slows down cognitive decline (Lautenschlager and Almeida,
2006). It is possible that the cyclical model which Lang and col-
leagues outlined may also be amended to include cognitive decline
such that perception of weakness causes older adults to both limit
their physical activity and to become objectively weaker therefore
848 D.A. Robertson et al. / Ageing Research Reviews 12 (2013) 840851
Neuropathology
Cognitive
Decline
Anorexia of
aging
Total Energy
Cardiovascular Expenditure
Risk Factors /
Disease
Social engagement
Activity Walking Speed
Disability
Dependency
Fig. 1. The cycle of frailty and cognitive impairment. Fried et al.s (2001) model is outlined in the grey shaded boxes. Our additions to this model are the mental health cycle
outlined in red (dashed) and the cognitive decline cycle outlined in blue (dotted) lines.
losing the benets that physical activity had on maintaining cogni-
tive function. Limited physical activity may be reduced further by
social isolation, a known contributor to both frailty and cognitive
decline. In a longitudinal study of non-institutionalized adults aged
62+ depression and social isolation were signicant risk factors for
developing frailty at follow up while data from the Canadian Study
of Healthy Ageing reported that individuals who scored highly on a
social vulnerability index had a 36% increased chance of experienc-
ing cognitive decline at 5 year follow up (Andrew and Rockwood,
2010; Strawbridge et al., 1998). Interestingly, the social vulnera-
bility index was most highly associated with poor performance in
executive function and verbal uency but not in measures of mem-
ory and other cognitive domains (Andrew et al., 2011). However
this nding was based solely on cross-sectional data and thus it is
not clear whether the impairments were long-standing or newly
developed as a cause of the social vulnerability. It is, however, an
area which merits further investigation given the evidence for an
association between frailty and impairment to executive function.
(We have included Fig. 1 to highlight the associations between
these and all other possible causal mechanisms).
5. Interventions
Although evidence for interventions into frailty coupled with
cognitive decline is limited, a small number of studies point to the
cognitive benets of physical activity. A 2010 review found that
physical activity protected against both sarcopenia and cognitive
decline in experimental training trials and in observational stud-
ies (Landi et al., 2010). Furthermore, a number of studies showed
that aerobic exercise training could reduce levels of both CRP and
IL-6 in middle-aged or older persons suggesting that the positive
effects of the physical exercise training may be through a reduc-
tion of inammation. We found one intervention study for frailty
and cognitive decline which was consistent with our criteria of an
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Downregulation of
Depression neurotransmitter systems
(e.g NA and DA)
Decreased
Motivation
Chronic Undernutrition Oxidative
[inadequate intake of protein and Stress
energy; micronutrient deficiencies]
Weight
Neuroendocrine Dysregulation - loss
Inflammation
testosterone, insulin, cortisol
Resting Metabolic Rate Sarcopenia
VO2 Max
-Senescent
muscoskeletal
changes
-Disease
Strength and
Power
Perceived Effort
operationalised denition of frailty. Langlois et al. (2013) found that
an aerobic exercise and strength training programme for both frail
and non-frail elderly adults over the course of 12 weeks improved
scores in functional capacity and physical endurance (although
not grip, gait or mobility), cognition and quality of life (Langlois
et al., 2013). The signicant improvements in cognition were due
to increased scores in measures of working memory, processing
speed and executive function. The improvements in quality of life
centred on personal and social components of quality of life such
as relationships, leisure activities and perceived physical health
rather than abilities such as managing nances or housekeeping.
Considering the suggested association between social vulnerabil-
ity, frailty and cognition, it is important that future studies untangle
the effects of physical activity from the increased social activity
which may have improved mood and self-perception, decreased
social isolation and led to reduced subjective weakness. Although
much larger, and many more, intervention studies will be required
before we can suggest that physical activity is benecial to partici-
pants with frailty and cognitive impairment, it is a promising start
to interventions in these two debilitating conditions.
6. Conclusions
Brain health is strongly linked to physical health, and physi-
cal function is, to a large extent, cognitively mediated. It should
therefore be no surprise that physical frailty and poor cognitive
function are related. Frieds denition of frailty is composed of ve
parts and each of these, individually, has previously been found to
be associated with cognitive decline. It is thus not surprising that
combining these elements together will create a measure that pre-
dicts cognitive decline. However, this denition of frailty was not
envisioned as a collection of symptoms, but rather as a collection
of indicators of an underlying syndrome which involves cumula-
tive decline or failure across multiple physiological systems. Fried
 D.A. Robertson et al. / Ageing Research Reviews 12 (2013) 840851
described the ve components as the end point of frailty, that is
the point at which somebody has already experienced the fail-
ure in multiple systems, and the point at which this collection of
symptoms becomes clinically apparent (Fried et al., 2001). It is this
concept which makes the Song et al. (2011) and Rockwood et al.
(2007a), denitions of frailty particularly interesting in light of cog-
nitive impairment. These denitions capture frailty at a point at
which the decline in multiple symptoms is still occurring either at
clinical or subclinical level. The Song et al. nding, that it is not
the type of decits which one measures which predict cognitive
decline but rather the number of decits, even those not tradi-
tionally associated with cognition, is particularly interesting as it
illustrates that it is likely the underlying frailty, and not simply the
symptoms of Frieds denition of frailty, which are linked to cog-
nitive decline. Unlike the Fried denition of frailty, therefore, the
denition used by Song et al. cannot be thought to be linked to cog-
nitive impairment through mechanisms already understood to link
physical and cognitive function such as low levels of activity and
muscle wastage.
A number of mechanisms AD pathology, hormones, nutri-
tion, chronic inammation, cardiovascular risks and mental health
have been proposed to explain the link between frailty and
cognition. It is likely that a number of factors contribute to
the relationship. Alzheimers disease pathology may lead to
frailty independently of cognitive function. Frailty and cognitive
impairment share risk factors such as chronic disease and poor car-
diovascular health, inammation, or hormonal dysregulation. Both
frailty and cognitive impairment can lead to, or be caused by, social
isolation, and it is likely that behavioural changes as a result of
cognitive impairment contribute to frailty through limited physical
activity and impaired nutrition.
Epidemiological studies have established the link between
frailty and cognitive domains of executive function, attention and
processing speed, and have provided some evidence that frailty can
be an early indicator for subsequent cognitive decline even after
taking account of baseline cognitive function. However, more work
on the predictive value of frailty measures in identifying those at
risk of preventable cognitive decline is needed.
Understanding how and why frailty is linked to cognitive
impairment has implications for the management of patients with
dementia and MCI and for older people in general. Frailty leads
to disability and loss of independence and so those with cogni-
tive impairment should be assessed for frailty in order to maintain
independence for as long as possible. If frailty is shown to lead to
cognitive impairment, then interventions to reduce frailty may be
targeted at the frail with the goal of preventing or even reversing
further cognitive decline.
Finally, there are some fundamental questions which remain to
be explored. Studies of the relationships between specic aspects of
frailty and cognitive impairment are inconsistent. Further studies
are needed to determine which measures of frailty could be used
to best identify those at risk of cognitive decline over the course of
ageing and vice versa. A better understanding of the direction of the
relationship between frailty and cognition and the specic aspects
involved, will help to validate the causative hypotheses outlined in
this paper and suggest, crucially, what interventions may be able
to break the frailty cycle.
Funding
This work was supported by Irish Life, the Department for Health
and Children, a Health Research Board grant (HRA PHS/2011/26)
and The Atlantic Philanthropies. No funding body had any say
in how this study was conducted or in how the manuscript was
written.
Descargado de ClinicalKey.es desde Universidad Nacional Autonoma de Mexico febrero 01, 2017.
Para uso personal exclusivamente. No se permiten otros usos sin autorizacin. Copyright 2017. Elsevier Inc. Todos los derechos reservados.
849
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