Invited Article

Harnessing brain and cognitive reserve for the prevention of dementia

Michael Valenzuela, Perminder S. Sachdev
School of Psychiatry, University of New South Wales, Sydney; Neuropsychiatric Institute, Prince of Wales Hospital,
Randwick, Australia
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ABSTRACT

The concepts of brain and cognitive reserve capture several elements of common wisdom – that we all differ in the
neural resources we are endowed at birth, that experience and especially complex mental activities then modify how
these neural resources are organized and cultivated, and that after any form of brain injury there is significant individual
variation in the degree to which clinical deficits may manifest. Transforming these insights into a formal and refutable
working definition, however, has been more challenging. Depending on the scale of analysis, brain and cognitive reserve
have been defined from neurocentric, neuropsychological, computational, and behavioral perspectives. In our research,
we have focused on the behavioral definition, whereby an individual’s lifetime exposure to complex mental activities
is used for prediction of longitudinal cognitive and neurological change. This approach also benefits from a wealth of
epidemiological studies linking heightened complex mental activity with reduced dementia risk. Research in the field
of cognitive training is also beginning to indicate that incident cognitive decline can be attenuated, with recent clinical
trials addressing the major challenges of transfer of gain and durability of effect. High quality randomized clinical trials
are therefore the most urgent priority in this area so that the promise of brain and cognitive reserve can be harnessed for
the purpose of the primary prevention of dementia.

Key words: Brain reserve, cognitive exercise, cognitive reserve, cognitive training, dementia, prevention

WHAT IS RESERVE? throughout their neocortex in comparison to those who

While most neuroscientists and clinicians would agree that
the brain has reserve capacity, the concept remains difficult
to define. What exactly is it that researchers mean when
invoking ‘reserve’? Part of the difficulty results from the fact
that this question can be approached from many angles.
These are briefly outlined below.
Neurocentric perspective
expressed clinical symptoms, suggesting that the lack of
symptoms in the former was because of a ‘greater reserve’.
The neurocentric version of brain reserve therefore implies
an advantage based on increased neuronal numbers. This
interpretation was also consistent with action of a linear
threshold mechanism,[2] whereby either a larger static
lesion, or the more protracted course of a progressive
lesion, was required before an individual may cross below a
hypothetical functional threshold.

Katzman et al.[1] first noted that cognitively normal
individuals with elevated Alzheimer’s disease (AD) pathology
had almost double the number of large pyramidal neurons
Address for correspondence: Dr. Michael Valenzuela,
Neuropsychiatric Institute, Prince of Wales Hospital, Randwick,
Sydney NSW 2031, Australia. E-mail: michaelv@unsw.edu.au
How to cite this article: Valenzuela M, Sachdev PS. Harnessing
brain and cognitive reserve for the prevention of dementia.
Indian J Psychiatry 2009;51:S16-21.
Since neuronal counts are not possible in life, clinical
studies have often relied on brain volume as a marker of
such reserve capacity. Use of a gross measure such as whole
brain volume, however, risks confusing a predictor variable
(one’s estimate of reserve) with a known outcome variable
(age-related cerebral atrophy). An alternative that has been
explored in the context of dementia is intracranial volume
(ICV) as a proxy for maximal brain volume, and even head
circumference[3] and head width[4] as more basic measures.
In general, these studies have failed to show a general
association with dementia incidence across the full range of
ICV, but rather an increased risk only in the low to very low

S16 Indian J Psychiatry 51: Supplement, January 2009

 Valenzuela and Sachdev: Cognitive reserve and prevention of dementia
ranges[5] or when in the presence of an additional risk factor
such as ApoE4.[3]
An obvious problem for the neurocentric interpretation
relates to the implication that brain reserve is a non-
modifiable entity. Maximum ICV and head circumference are
generally achieved by puberty[6] and reflect genetic variance
in neuronal quantum as well as developmental, nutritional,
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and environmental factors in early life.[7] More importantly,
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since these measures do not generally change after the
onset of adulthood, does this mean that underlying brain
reserve can also not change? As will be reviewed below, the
weight of evidence from the epidemiological, clinical, and
experimental literature suggests the opposite. Dementia
risk appears to be highly modifiable by experience well into
late life. For these reasons, a neurocentric version of brain
reserve is not tenable, although it is important to note that
this reflects current technological limitations rather than
any underlying conceptual flaw. Brain reserve, of whatever
flavor, must at some level have a neurobiological correlate.
Cognitive perspective
Rather than focus on the maximal quantity or volume of
neurons, the cognitive reserve perspective is more interested
in ‘how well we use what has been left behind’.[8,9] Two non-
trivial distinctions have been made. First, we could replace
“neuronal numbers” with “neuropsychological competence”
or “intelligence”, and so apply a similar threshold mechanism
whereby high cognitive reserve individuals simply perform
better on cognitive tests to start with and therefore
require a larger fall before reaching diagnostic threshold.
Importantly, this account suggests no interaction with the
underlying and progressive neurodegenerative process, and
so predicts no differential rate in cognitive decline, only
different starting points for the decline. It has therefore
been termed a passive account[8] and been identified as
a potential source of systematic error in longitudinal
studies.[10] Clearly, in the context of ageing and dementia,
any reserve definition must be able to independently
predict differential rates of neuropsychological change, not
just differences in incidence of impairment.
Alternatively, a more dynamic form of cognitive reserve
suggests that individuals who have developed a range
of deliberate cognitive strategies for solving complex
problems, such as navigating around the neighborhood,
and perform well on neuropsychological tests, are more
likely to remain within normal limits for longer despite
the parallel progression of underlying disease. This active
account therefore suggests that two individuals may
begin at the same neuropsychological starting point and
suffer the same longitudinal burden of disease, but due to
increased strategic mechanisms, one may perform better at
follow-up testing, or suffer from less day-to-day symptoms.
Whilst capturing part of the ecological nature of reserve,
Indian J Psychiatry 51: Supplement, January 2009
this definition is extraordinarily difficult to measure. Simply
asking subjects about their use of deliberate strategies whilst
performing memory tasks can, for example, produce more
questions than answers.[11] On the other hand, if we assume
that one’s capacity for deliberate cognitive flexibility is akin
to greater problem solving or ability to set-shift, we again
risk confounding a predictor with an outcome variable (i.e.,
age-related decline in executive functions).
Computational perspective
A more sophisticated approach to reserve revolves around
the notions of computational redundancy and flexibility. High
cognitive reserve individuals may not only have a wider
repertoire of conscious and preconscious strategies, but
also a greater number of potential neural pathways for
execution of these cognitive processes, thus allowing
maintenance of function despite neurological insult. A person
with high reserve and high disease burden may therefore
remain asymptomatic due to compensatory and resistant
adaptations to functional brain networks; alternatively, a low
reserve individual may express symptoms after only a trivial
brain insult due to a lack of redundant neural pathways and
an inflexible or intolerant functional network.[12,13]
Whilst this approach is attractive as it unifies brain and
cognitive reserve with a specific mechanism, problems with
operationalization again arise. Do we attempt to estimate
neurocomputational factors such as network efficiency
and redundancy via some type of functional neuroimaging
‘stress test’? Whilst of high interest, a working definition of
brain reserve along these lines is currently not practical.
Behavioral perspective
The strategy adopted in our research has been a behavioral
one and simply asks how mentally active and engaged a
person is in comparison with the average? It therefore seeks
a reliable definition at the level of day-to-day observable and
verifiable facts related to complex mental activity. The type of
information relevant to this version of reserve includes level
and duration of formal education, the nature and complexity
of occupational history, and the diversity, frequency and
cognitive challenge of past and present leisure activities.
This has been combined into a validated assessment tool,
the Lifetime of Experience Questionnaire (LEQ),[14] which takes
15 min to complete and is now available online for research
use (http://train.headstrongcognitive.com/leq.aspx). Higher
LEQ scores independently predict not only attenuated
cognitive decline over time, but also a reduced rate of
hippocampal atrophy.[15] The main advantage from such a
straightforward formulation is therefore the provision of an
operational definition which is clinically relevant.
Importantly, this behavioral approach to measuring brain
or cognitive reserve does not identify itself with a specific
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 Valenzuela and Sachdev: Cognitive reserve and prevention of dementia
neurological quantum, computational property or cognitive
process. It seems self evident that participation in complex
mental activities will lead to changes in a number of interacting
mechanisms at different temporal and spatial scales,[12] which
together may alter an individual’s risk for dementia and
cognitive dysfunction. In our opinion, there is no one brain
or cognitive reserve, but a number of reserves.[16] Our working
definition is hence at the behavioral scale for essentially
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pragmatic reasons because it is arguably more amenable to
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precise characterization and hence general utility.
Links between mental exercise and
dementia risk
Several large-scale epidemiological studies have linked
participation in complex mental activity to reduced dementia
risk. A systematic review of 22 longitudinal cohort studies found
that individuals with higher levels of education, occupation or
engagement in complex cognitive activities were at 46% lower
risk for incident dementia than those with low levels.[17]
When restricting analysis to those cohort studies of older
persons that have focused on cognitive complexity in their
current lifestyle, protective effects remain significant even
after controlling for earlier life exposures such as education,
occupation, baseline cognition, and cardiovascular risk
factors.[18-22] Moreover, evidence for a dose dependent
relationship is evident from studies that show
corresponding decrements in dementia risk as a function
of increasing participation in cognitive lifestyle activities.[23]
For example, Verghese et al. found that compared to those
older individuals with the lowest level of participation in
cognitive lifestyle activities, those with moderate activity
levels had 50% lower risk for dementia over 5 years follow-
up, and those with the highest activity levels had 67% lower
risk for incident dementia.[24]
There is now highly consistent epidemiological support
for an association between complex mental activity and
dementia risk, but the nature of the relationship remains
contentious for two main reasons. First, the biological
mechanisms which may mediate a nexus between mental
activity and dementia are not clear. Some potential
mediating mechanisms are briefly reviewed below. Second,
and more importantly, there are questions about the direction
of causality: does preceding mental activity reduce or delay
expression of future dementia or is preclinical dementia
causing a reduction in participation in activities prior to
formal diagnosis? To disentangle this complex ‘chicken or
egg’ problem, data from clinical trials using cognitive training
interventions are required.
Clinical trials of cognitive training
Definition of cognitive training
Cognitive training is any intervention aimed at improving,
S18 Indian J Psychiatry 51: Supplement, January 2009
maintaining, or restoring mental function through the
repeated and structured practice of tasks which pose
an inherent problem or mental challenge. Importantly,
this definition does not include training in strategies to
compensate for deficits, traditionally a rehabilitative or
remedial approach.[25]
Randomized controlled trials in late
life
Repetitive cognitive training undoubtedly improves
performance on the trained task – there is indeed more than
20 years of cognitive psychology research on this topic.[26]
To determine whether cognitive training could potentially
help reduce or delay the incidence of dementia, two major
issues need consideration:
1) Generalization or transfer of effect
Does the cognitive training intervention only lead
to improvement in the trained task, or does it also
transfer to non-trained tasks? We propose a hierarchy
of generalization of increasing clinical relevance:
a. Transfer to non-trained tasks in same cognitive
domain
b. Transfer to non-trained tasks in other cognitive
domains
c. Transfer to global measures of general cognitive
ability (e.g., Alzheimer’s disease assessment scale -
cognitive, tests for general intellectual ability, etc.)
d. Transfer to measures of general function (e.g.,
instrumental activities of daily living, quality of life,
mood, etc.)
2) Persistence or durability of effect
Does the effect of cognitive training intervention
last beyond the immediate post-training period, or
is continual cognitive training required? Longitudinal
follow-up of cognitive training efficacy is required to
answer this question.
We have recently published a systematic review of
randomized controlled trials (RCT) of cognitive training
in healthy older individuals in which longitudinal follow-
up was a critical design feature.[27] The results of seven
identified trials suggest that a discrete program of cognitive
exercise in the order of 2-3 months may have long-lasting
and persistent protective effects on cognition over a number
of years. The overall weighted mean difference was strong
in magnitude, estimated at 1.07 (CI: 0.32-1.83); the overall
non-weighted average Cohen’s d effect size was 0.5.
The ACTIVE study is the largest trial in the area[28] and
examined the effects of 10 sessions of cognitive training
on 2832 healthy older individuals. Participants completed
three different intervention groups: memory training,
reasoning training, and processing speed training. Two
years later, each intervention improved cognitive ability
 Valenzuela and Sachdev: Cognitive reserve and prevention of dementia
in the targeted area. Importantly, at this stage there was
no evidence of transfer of gain to other domains, nor any
effect on instrumental activities of daily living. Follow
up at five-years, however, found that reasoning training
specifically protected against functional decline compared
to any of the other interventions or the control wait-and-
see condition.[29] This is therefore the first large clinical trial
to demonstrate transfer of effect since cognitive training
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produced enduring benefits on a general functional outcome
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that is highly relevant to dementia onset.
There is also a high degree of community and commercial
interest in computer-based cognitive training. One group
has conducted a RCT with one such product in a report
that included co-authors from the parent company.[30] The
attraction of computerized cognitive training is that training
can be standardized and allows a gradient in task difficulty
to be incorporated as individuals’ skill levels progress.
Neuropsychological tests immediately after the end of
the training period found verbal memory performance
improved by up to 25% of a standard deviation, and testing 3
months later showed that short-term memory performance
remained enhanced.
The combination of both cognitive and physical exercise
is also of great interest. This has yet to be tested in a
rigorous RCT. The Sim-A study investigated the effects
of cognitive, physical, and combined training in healthy
older individuals over a five year period.[31] Thirty
paper-and-pencil cognitive training sessions produced
a significant effect over both the 12 month and 5-year
follow-up periods. Moreover, this effect seemed to
transfer to a measure of general cognition. The group
that did both cognitive and physical training experienced
a larger effect size than those who completed just one
type of training, suggesting a potential for synergy
between these modalities. Other smaller studies with
samples of less than 100 individuals have found positive
trends but have lacked power.[32,33]
The overall effect size and consistency across longitudinal
trials of cognitive training is therefore promising, yet
many questions remain. There has been a wide variety of
primary outcome measures, for example, across the trials,
and details of the applied cognitive tasks also varied.
Quality of trial design and reporting has in general been
low.
It is however encouraging that those studies with longer
term follow-up showed no evidence of less potent effects.
A durable long-term effect from cognitive training may
therefore be realistic. Finally, two of the more recent
clinical studies have shown that their training protocols
generalize to domains beyond the narrow focus of the
trained tasks.[29,31] Well designed cognitive training
interventions may thereby have the potential to contribute
Indian J Psychiatry 51: Supplement, January 2009
to primary prevention of dementia as part of a holistic risk
reduction strategy.
How could mental exercise prevent
dementia?
Complex mental activity clearly alters the structure and
function of the brain on a number of levels. We have
previously reviewed how the spatial and temporal nature
of these changes may contribute to defense against
dementia,[12] with information gained mainly from decades
of work studying the effects of enrichment on the rodent
brain[34] and from human brain imaging. Here, we present a
highly condensed summary.
Molecular mechanisms
Short periods of increased activity alter long-term
potentiation and depression,[35] possibly by upregulation
of AMPA receptors.[36] Neurotrophic hormones are also
increased, particularly BDNF[37,38] and NGF.[39] Strikingly,
transgenic Alzheimer model mice show dramatic decrements
in pathology[40-42] and improvements in behavior[43]
after several weeks of enrichment compared to control
littermates. The time frame for detection of biological
changes secondary to enrichment is minimal, given that
microarray analysis has shown dozens of gene expression
changes following as little as three hours of exposure.[44]
Cellular mechanisms
Synaptogenesis is arguably the most robust cellular change,
in the order of 150-300%,[45] and potentially the most
clinically relevant, as decline in synaptic density is strongly
correlated with cognitive status in dementia.[46] Experience-
dependent neurogenesis[47] and angiogenesis[48] also occur,
which in combination may explain why enrichment seems to
lead to increased gross brain volume,[7] as well as increased
regional volumetric changes in humans.[49,50]
Cortical network mechanisms
Repeated cognitive exercise leads to increased metabolic
efficiency across whole brain networks,[51] whilst selectively
and temporarily increasing haemodynamic responsivity in
brain areas engaged by the cognitive tasks.[52,53] There is also
evidence for an enhanced ability to adapt and compensate
against progressive disease in the medial temporal lobe,
particularly through functional reorganization in the
prefrontal cortex.[54-57]
Recommendations and challenges for the future
A confluence of research streams has emerged in the last
10 years as the basis for intense medical, community and
commercial interest in trying to harness the power of brain
and cognitive reserve for the prevention of age-related
cognitive dysfunction. Perhaps the greatest influence has
been a wider sociological trend away from pharmacological
agents and towards behavioral and lifestyle modification and
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 Valenzuela and Sachdev: Cognitive reserve and prevention of dementia
positivistic health attitudes. Yet this enthusiasm should not
obscure our demand for rigorous scientific evidence when
attempting to translate preclinical findings to individual and
community-wide interventions. The greatest challenges for
the area are therefore in the domain of clinical trials. No trial
has, for example, definitively shown that cognitive training
reduces the incidence of dementia, as opposed to the rate
of cognitive decline. Higher caliber RCTs are required, with
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close attention to design of control groups, longitudinal
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evaluation, choice of cognitive training protocol and
outcome measures, and recruitment of relevant samples.
This information will then need to inform wider community
programs, and many more questions arise. For example,
is starting a new cognitively demanding hobby as good as
many hours of computer-based cognitive training? If so,
are all activities equally effective or only some? How often
and what intensity of engagement is required? Is group
participation better than individual practice at home?
Generic issues will also arise such as scalability, accessibility,
economy, and accountability.
In the meantime, the general public needs to be well
informed about the links between complex mental activity
and reduced dementia risk. Given the negligible potential
for harm, it is sensible to encourage all individuals to
increase their levels of complex, enjoyable, and engaging
cognitive activity for optimal brain health, particularly after
retirement.
ACKNOWLEDGMENT
We thank, National Health and Medical Research Council of
Australia program for the grant #350833. MV is a University of
New South Wales Vice Chancellor’s research fellow.
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Source of Support: National Health and Medical Research
Council of Australia program grant #350833.
Conflict of Interest: None declared
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