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REVIEWS

Cognitive intervention in Alzheimer disease


Verena Buschert, Arun L. W. Bokde and Harald Hampel
Abstract | Alzheimer disease (AD) is one of the most prevalent chronic medical conditions affecting the elderly
population. The effectiveness of approved antidementia drugs, however, is limited—licensed AD medications
provide only moderate relief of clinical symptoms. Cognitive intervention is a noninvasive therapy that could
aid prevention and treatment of AD. Data suggest that specifically designed cognitive interventions could
impart therapeutic benefits to patients with AD that are associated with substantial biological changes within
the brain. Moreover, evidence indicates that a combination of pharmacological and non-pharmacological
interventions could provide greater relief of clinical symptoms than either intervention given alone. Functional
and structural MRI studies have increased our understanding of the underlying neurobiological mechanisms of
aging and neurodegeneration, but the use of neuroimaging to investigate the effect of cognitive intervention on
the brain remains largely unexplored. This Review provides an overview of the use of cognitive intervention
in the healthy elderly population and patients with AD, and summarizes emerging findings that provide
evidence for the effectiveness of this approach. Finally, we present recommendations for future research on
the use of cognitive interventions in AD and discuss potential effects of this therapy on disease modification.
Buschert, V. et al. Nat. Rev. Neurol. 6, 508–517 (2010); published online 17 August 2010; doi:10.1038/nrneurol.2010.113

receptor antagonist—provide only limited relief from


Continuing Medical Education online
clinical symptoms and, on average, delay cognitive decline
This activity has been planned and implemented in accordance by only 6–12 months.2 Thus, new therapeutic strategies are
with the Essential Areas and policies of the Accreditation Council urgently needed that robustly inhibit the clinical symptoms
for Continuing Medical Education through the joint sponsorship of
Medscape, LLC and Nature Publishing Group. Medscape, LLC is
of AD and attenuate disease progression. Cognitive inter-
accredited by the ACCME to provide continuing medical education vention seems to be an emerging therapeutic approach
for physicians. that could aid prevention and treatment of this disease.
Medscape, LLC designates this educational activity for a maximum Research suggests that regular activation of various brain
of 1.0 AMA PRA Category 1 CreditsTM. Physicians should only claim networks by cognitive and/or physical stimulation could
credit commensurate with the extent of their participation in the
Dementia Research considerably contribute to brain health and cognitive
Section and Memory activity. All other clinicians completing this activity will be issued
Clinic, Alzheimer a certificate of participation. To participate in this journal CME status.3,4 Moreover, approaches that combine pharmaco-
Memorial Center and activity: (1) review the learning objectives and author disclosures; logical and non-pharmacological interventions might
Research Section, (2) study the education content; (3) take the post-test and/or effectively support cognitive, affective and functional abili-
Department of complete the evaluation at http://www.medscapecme.com/journal/
Psychiatry, Ludwig- nrneuro; and (4) view/print certificate.
ties in patients with preclinical or clinical AD. Compared
Maximilian University, with pharmacological treatment of AD, cognitive inter-
Nussbaumstrasse 7, Learning objectives
D-80366 Munich,
ventions are likely to be less expensive and more cost-
Upon completion of this activity, participants should be able to: effective,5 in addition, cognitive intervention is thought
Germany (V. Buschert).
1 Identify the factor that is associated with the maintenance
Discipline of Psychiatry,
of cognitive reserve and incorporate this knowledge into to cause no adverse events.6
School of Medicine &
Trinity College Institute strategies for the prevention of dementia. In this article, we review the use of cognitive intervention
of Neuroscience, 2 Examine cognitive interventions for the management of in healthy elderly individuals and patients with preclinical
Cognitive Systems Alzheimer’s disease, and develop treatment strategies that
Group, Trinity College
or clinical AD, and provide an overview of recent studies
correctly incorporate these interventions.
Dublin, Lloyd Building, that suggest that cognitive intervention provides sub-
Dublin 2, Ireland
stantial benefits for patients with this condition. We also
(A. L. W. Bokde).
Department of Introduction present recommendations for future research on the use of
Psychiatry, Alzheimer disease (AD) is one of the most devastat- cognitive interventions in AD and discuss how this non-
Psychosomatic
Medicine & ing and prevalent chronic medical conditions in elderly pharmacological treatment can modify clinical symptoms
Psychotherapy, Johann individuals.1 At present, no approved disease-modifying associated with this disease.
Wolfgang Goethe
University, Heinrich-
drugs are available for this condition. Licensed anti-
Hoffmann-Straße 10, dementia drugs, such as cholinesterase inhibitors Neuronal plasticity
60528 Frankfurt, (ChEIs) and memantine—an N-methyl-d-aspartate Evidence for the usefulness of cognitive interventions in
Germany (H. Hampel).
AD originates from several different areas of research, and
Correspondence to:
Competing interests
the assertion that cognition-based interventions could
V. Buschert
verena.buschert@ The authors, the journal Chief Editor H. Wood and the CME impart therapeutic benefits to patients with this disease
med.uni-muenchen.de questions author C. P. Vega declare no competing interests. derives from the concept of neuronal plasticity. Neuronal

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plasticity can be defined as the ability of the nervous Key points


system to adapt its structural organization in response
■ No disease-modifying drugs are available for the treatment of Alzheimer disease
to changes in the environment, as well as other factors (AD) and the effectiveness of approved antidementia drugs is still not satisfactory
such as injuries, which affect the integrity and functioning
■ Non-pharmacological interventions could aid the prevention and treatment of AD,
of the nervous system.7 Neuronal plasticity is considered and combining pharmacological and non-pharmacological interventions might
to be an essential process that endows animals—in par- substantially alleviate the clinical symptoms associated with the disease
ticular, humans and other primates—with the ability to ■ Neuroimaging studies could further our understanding of the neurobiological
adapt to new cognitive or behavioral stresses. A high mechanisms underlying the effects of cognitive intervention on the brain
level of neuronal plasticity, although deemed integral to
■ Health-care professionals must base recommendations concerning the use
brain evolution, has been shown to be associated with of cognitive intervention in mild cognitive impairment and AD on robust
increased neuronal vulnerability in regions of the brain experimental evidence
that are typically affected in AD.8 This finding suggests ■ No standardized intervention programs are currently available for the treatment
that a complex relationship exists between this aging- of the diverse cognitive and functional impairments associated with the different
associated, chronically progressive disease of the CNs stages of AD
and the genetic, epigenetic, functional, metabolic and
structural changes that have taken place throughout the
evolution of the human brain.9 Although a high degree of cog nitive decline once dementia has been clinically
neuronal plasticity could contribute to the clinical symp- diagnosed. In fact, findings from neuroimaging studies
toms associated with AD, enhancing neuronal plasticity, support the concept that cognitive reserve can attenuate
especially in higher-order frontal, parietal and temporal the clinical symptoms associated with dementia and con-
association cortices might improve neurological function- tribute to the neurophysiological heterogeneity observed
ing and could prevent the loss of neuronal processes that in AD.8
typically occurs in AD.10 Brain reserve is also hypothesized to affect an indivi-
dual’s risk of cognitive decline. In contrast to cognitive
Cognitive reserve and brain reserve reserve, brain reserve is considered to be a passive quality,
Meta-analyses have provided strong evidence that speci- and is thought to be directly related to brain size or neu-
fically designed cognitive training programs can attenuate ronal cell count. Brain reserve influences the amount
the risk of cognitive decline in healthy elderly patients.11 of brain damage that can be sustained before clinical
The beneficial effects of cognitive training are thought to symptoms develop.13
reflect increases in cognitive reserve. Cognitive reserve
relates to the brain’s ability to perform cognitive tasks Physical exercise
adequately despite neuropathological damage,12 and is Physical exercise seems to have a beneficial effect on cog-
thought to represent either an enhanced ability to recruit nition.16 Accumulating evidence from animal studies and
alternative brain networks or a more efficient utilization epidemiological studies in humans indicates that mod-
of brain networks in general.13 These proposed mecha- erate exercise improves cognitive function in normal
nisms are both considered to require neuronal plas- individuals,3 is neuroprotective in healthy animals and
ticity. Education, mentally demanding occupations and humans, and can prevent cognitive decline in patients
mentally stimulating lifestyle pursuits are all thought to with AD.17–22 Nevertheless, owing to the limited number
increase cognitive reserve.14 Individuals deemed to have of randomized controlled trials that have been conducted
greater reserves have been shown to have a reduced risk of to investigate the effects of physical activity on cognition,
developing dementia compared with individuals judged the authors of a systematic review on this subject have
to have low reserves,13 and studies have demonstrated concluded that insufficient evidence exists to suggest that
that higher cognitive reserve is associated with increased physical activity is beneficial for people with dementia.23
cognitive performance in healthy elderly people.12,15,16 Additional studies are necessary before any potential
The effects of cognitive reserve can be substantial. effects of exercise on cognition in patients with AD or
A meta-analysis including over 29,000 individuals has mild cognitive impairment (MCI) are recognized. We
shown that individuals with high cognitive reserve had believe that comparing the efficacy of physical exercise
a 46% reduced risk of developing dementia compared programs with cognitive intervention programs in clini-
with individuals with low cognitive reserve.14 of all cal and preclinical AD and evaluating the combination of
the factors that influence cognitive reserve, mentally both interventions would be extremely instructive.
stimulating activities were shown to have the largest
effect on dementia risk. The effect of cognitive reserve Terms and definitions
was sustained over a median longitudinal follow-up of With regard to the use of cognition-based activities in
7 years. As cognitive reserve seems to have such a large AD, terms like cognitive training, cognitive rehabilita-
effect on the risk of developing dementia, cognitive tion and cognitive stimulation have been used almost
interventions—secondary prevention or rehabilitative interchangeably in the literature. Although cognitive
measures—might attenuate cognitive decline in patients training and cognitive rehabilitation are related, they
with dementia. Moreover, cognitive interventions could are, in fact, two different forms of cognitive interven-
potentially delay the onset of dementia and might also tion, both of which are also distinct from cognitive
be able to partially reverse neurodegenerative-related stimulation (Box 1).24 Cognitive stimulation comprises

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Box 1 | Definition of cognitive interventions25 with clinical cognitive deficits or dementia have been
considered in this Review.
Cognitive training Cognition-related intervention strategies can be
■ Guided practice on a set of standard tasks designed to increase particular divided into two basic categories: compensatory strat-
cognitive functions; for example attention, memory and problem-solving egies and restorative strategies.4 The aim of compensatory
■ By improving cognitive abilities, accomplishment of everyday tasks and strategies is to teach patients with cognitive deficits new
independent living are supported ways of performing cognitive tasks by changing every-
■ Generalized effects beyond the immediate training context are envisaged day memory behavior, so that they can ‘work around’
Cognitive rehabilitation their cognitive deficits. This approach emphasizes the
■ Individualized approach in which personally relevant goals are identified, and
use of internal strategies such as organizing information
the therapist works with the patient and their family to devise strategies to to be remembered, or encoding information through
address these goals multiple sensory modalities such as visual and auditory
■ Emphasis is placed on improving performance in everyday life rather than on senses, but also includes the use of electronic and non-
cognitive tests, thereby building on the individual’s strengths and developing electronic memory aids, as well as procedural training
ways of compensating for impairment (Box 2). By contrast, the aim of restorative strategies is to
■ Changes instituted in one setting would not necessarily generalize to another enhance functioning in specific cognitive domains, with
the goal of returning cognitive function to premorbid
Cognitive stimulation
levels.4 These two approaches can be used separately
■ Engagement in a range of activities aimed at general enhancement of cognitive or in combination. For example, the errorless learning
and social functioning in a nonspecific manner
approach is often combined with the spaced retrieval
■ Usually administered in a group setting technique (Box 2). some evidence indicates that restora-
tive strategies used in cognitive intervention programs
for the treatment of patients with mild-to-moderate AD
Box 2 | Compensatory and restorative cognitive intervention strategies4 achieve greater improvements in cognitive functioning
than do compensatory approaches.4,26
Compensatory strategies
■ Encoding specificity:77 interactive encoding and retrieval by encoding further Cognitive training in healthy elderly
cues such as semantic classification within the context (for example, target Numerous studies have shown that cognitive training
word: carrot; additional cue: vegetable) benefits healthy elderly individuals. 27,28 However, the
■ Visual imagery:78 simultaneous association of new verbal material (semantic opinion that commercially available computerized brain-
memory) and visual information during encoding training programs improve general cognitive function in
■ External memory aids: electronic notebook,79 notes, calendars and prompts80 the wider population lacks empirical support.29 Regard-
■ Dyadic approach: instructing the patient’s caregiver to carry out various ing the potential use of cognitive training in patients with
memory and cognitive improvement strategies AD, the few clinical trials that have been conducted to date
Restorative strategies have addressed two key issues: persistence of effect over
time, and transfer of effect to non-trained domains.11
■ Spaced retrieval technique:81 repeated recalling of information at short but
gradually increasing time intervals The sIMA (Maintaining and supporting Independent
Living in old Age) study demonstrated that a combina-
■ Vanishing cues technique:82 gradually giving as many letter prompts as required
by adding (forward cueing) and removing (backward chaining) cues until target tion of memory and psychomotor training significantly
word is correctly identified improved cognitive status in healthy elderly people
■ Errorless learning approach:83 elimination of incorrect or inappropriate
(75–89 years) after 1 year of training.16 This effect was
responses (interferences) during the learning process, and avoiding frustration stable for 5 years, and immediate and long-term transfer
and decreased motivation effects on non-trained cognitive functions were demon-
■ Sensorimotor skill stimulation: training of simple daily activities such as strated. In addition, all participants (aged 65–94 years)
grooming, preparing and eating meals and using a telephone, to improve in the ACTIvE (Advanced Cognitive Training for
daily living Independent and vital Elderly) study showed significant
■ Reality orientation therapy84 and reminiscence therapy:85 aims to improve improvements in distinct cognitive functions—memory,
temporal, local and personal orientation by proposal of orientation information, reasoning, problem solving and speed of processing—
either throughout the day or in group meetings on a regular basis after receiving >2 years of cognitive intervention therapy.30
11 month follow-up booster training sessions, which
were administered to over 60% of the study participants,
engagement in a range of activities that aim to enhance successfully improved reasoning and speed of processing
general cognitive and social functioning. Cognitive abilities. Improvements in these cognitive functions were
training, however, is a more specific approach, which stable for over 5 years. In addition, the 5 year follow-up
involves teaching patients strategies and skills in order revealed that reasoning training resulted in a reduced
to optimize specific cognitive functions. Cognitive reha- decline in ‘everyday’ functions.31 The positive effects of
bilitation is broadly defined as the use of any interven- cognitive training, such as delaying cognitive and func-
tion strategy that enables patients and their families to tional decline in healthy elderly adults, have substantial
manage the patient’s cognitive deficits.25 only approaches ramifications for its potential application in patients
that have been used to target cognitive deficits in patients with MCI.

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Table 1 | Cognitive intervention in patients with MCI and AD


Reference intervention (treatment Participants Duration Results
vs control)
Olazaran Cognitive (memory, attention, Total 84: 12 MCI, 48 mild AD, 1 year (103 twice- TG maintained cognitive status at 6 months;
et al. (2004)38 language, visuoconstructive 24 moderate AD; 44 TG, 40 CG weekly 310 min significant deterioration of CG at 6 months;
abilities and executive functions) sessions); TG maintained or improved affective status
and motor intervention plus no follow-up (GDS) at month 12
psychosocial activities
vs psychosocial support only
Belleville Teaching episodic memory Total 47: 20 MCI, 9 healthy (TG) Weekly 120 min Improvement of TG in delayed list recall and
et al. (2006)53 strategies, metacognition and vs 8 MCI, 8 healthy (CG); note sessions for face–name association; improved subjective
computer-based training of discrepancy between number of 8 weeks; memory and well-being
attention vs waiting-list group participants reported in each no follow-up
group and total number of
participants reported
Cipriani et al. Individualized computer-based Total 23: 10 MCI, 10 mild AD, Weekly sessions MCI: improvement in tasks concerning
(2006)41 cognitive training (no control group) 3 MSA; 20 TG, 3 CG* (13–45 min per day working memory and psychomotor function,
for 4 days) for improvement in behavioral memory;
8 weeks; AD: improved global cognitive status
no follow-up (MMSE), improved verbal production and
executive functions; MSA: no improvement
Rozzini et al. Computer-based cognitive training Total 59 MCI: 15 TG + ChEIs, Weekly sessions After 3 months follow-up, TG + ChEIs:
(2007)39 (memory, attention and language 22 ChEIs alone, 22 NT (60 min per day improvements in two different cognitive
training, abstract reasoning, for 5 days) for areas (memory, abstract reasoning) and
thinking, visuoconstructive 12 weeks; behavioral disturbances (depressive
abilities) and ChEIs vs ChEIs or NT 3 month follow-up symptoms); ChEIs alone: improvement in
depressive symptoms; NT: cognitive,
functional and behavioral status remained
unchanged
Talassi et al. Computerized cognitive training, Total 66: 30 MCI, 24 mild AD Weekly sessions MCI TG: improvement in constructive apraxia
(2007)40 occupational therapy and (TG) vs 7 MCI, 5 mild AD (CG) (30–45 min per day and long-term visuospatial memory, reduced
behavioral training for 4 days) for symptoms of depression and anxiety; mild
vs physical rehabilitation, 3 weeks; AD TG: improved global cognitive status
occupational therapy and no follow-up (MMSE), reduced symptoms of depression
behavioral training and anxiety; AD CG: improved word fluency
Troyer et al. Evidenced-based memory training Total 54 MCI: 27 TG, 27 CG 10 sessions TG: improved memory-strategy knowledge
(2008)42 aimed at teaching and practicing (120 min each) and use; no improvement in memory beliefs
of compensatory memory over 6 months; or objective memory performance
strategies and lifestyle education 3 month follow-up
vs waiting-list group
Kinsella et al. Evidenced-based memory Total 47 MCI: 22 MCI vs 25 MCI Weekly 90 min Improvements in performance on
(2009)43 rehabilitation aimed at teaching sessions for prospective memory tasks and knowledge
and practicing of all-day memory 5 weeks; and use of memory strategies
strategies 4 month follow-up
*MSA group served as the control group. Abbreviations: AD, Alzheimer disease; CG, control group; ChEIs, cholinesterase inhibitors; GDS, Geriatric Depression Scale; MCI, mild cognitive
impairment; MMSE, Mini Mental State Examination; MSA, multiple system atrophy; NT, no treatment; TG, treatment group.

Cognitive intervention domains,35 develop dementia within 1 year after being


Mild cognitive impairment diagnosed with this condition.36 Thus, compared with
Beneficial effects of cognition-based interventions healthy individuals of the same age, patients with MCI
on cognitive decline have been reported in patients who have noticeable deficits in memory37 can be regarded
with MCI.32 MCI is defined as a subjective complaint as having an increased risk of developing dementia.
of memory impairment with demonstrated objective The use of cognitive training in MCI has typically
memory deficits that does not interfere notably with focused on enhancing episodic memory by teaching
activities of daily life or psychosocial competence. patients learning strategies,27 making them perform cog-
Importantly, MCI does not fulfill the currently accepted nitive exercises, and increasing their levels of social and
clinical criteria for dementia, as defined by either the psychomotor activity (Table 1).38–41 A review on cogni-
Diagnostic and statistical Manual of Mental Disorders tive intervention in MCI indicates that cognitive training
(edition Iv) or the International Classification of is an efficient method of delaying cognitive decline in
Diseases (10th edition).33 According to population-based patients with MCI, and suggests that, following train-
epidemiological studies, the prevalence of MCI ranges ing, episodic memory improves, as does mood and
from 3–19% in the adult population aged >65 years in behavior.32 However, the few studies that were reviewed
the Western world.34 Furthermore, a meta-analysis has in the article had limited power owing to small sample
shown that 5–10% of patients with MCI, notably those sizes, and even fewer evaluated long-term effects or the
who have amnestic impairments in single or multiple global functional impact of cognitive training on patients

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Table 2 | Cognitive intervention in subjects with mild-to-moderate AD


Reference Conditions (treatment vs control) Participants Duration Results and comments
Spector et al. CS therapy (reality orientation) Total 201: Two 45 min sessions TG showed improved global cognitive functions
(2003)6 vs usual activities 115 TG, 86 CG per week for (MMST, ADAS-cog) and quality of life; number needed
7 weeks; to treat (6) (≥4 points on ADAS-cog) results compare
no follow-up favorably with trials of dementia drugs
Requena et al. ChEIs and CS involving images of Total 86: 12 months, weekly ChEI + CS and CS only: improved MMSE, ADAS-cog
(2004)45 everyday life and reminiscent music 20 ChEI + CS, (5 days each and FAST; ChEI only: improvement in affective
vs ChEI only vs CS only vs watching 30 ChEI only, 45 min); 1 year symptoms (GDS); NT: poor scores in all measures
television 18 CS only, 18 NT follow-up compared with other groups
Requena et al. ChEIs and CS involving images Total 68: 2 years, weekly Gradual deterioration in all groups; greater and faster
(2006)49 of everyday life and reminiscent 14 ChEIs + CS, (5 days each progress in patients not receiving any treatment
music vs ChEIs only vs CS only vs 20 ChEIs only, 45 min)
watching television 14 CS only, 30 NT
Farina et al. Procedural memory training (activities Total 22: Weekly sessions Both groups improved functional living skills; slightly
(2002)50 of daily living) vs training of partially 11 TG, 11 CG (each two 45 min improved performance in specific cognitive functions
spared cognitive functions sessions a day for (attention, verbal fluency); training in activities of daily
3 days) for 5 weeks; living might be more effective than stimulating
3 month follow-up ‘residual’ cognitive functions
Farina et al. Recreational activities, for example, Total 32: 6 weeks Global stimulation group: reduced behavioral
(2006)51 crafts, games, pets and ROT (global 16 TG, 16 CG (15 sessions disturbances (NPI); reduced memory behavioral
stimulation) vs combination of each 180 min); problems; improved functional living skills; improved
procedural memory training on 6 months follow-up verbal fluency; at 6 months follow-up, alleviation of
activities of daily living and caregiver distress (NPI) associated with global
neuropsychological rehabilitation of stimulation group
‘residual’ functions (cognitive-specific)
Abbreviations: AD, Alzheimer disease; ADAS-cog, Alzheimer’s Disease Assessment Scale Cognitive Subscale; ADL, activities of daily living; CG, control group; ChEIs, cholinesterase inhibitors;
CS, cognitive stimulation; GDS, Geriatric Depression Scale; FAST, Functional Assessment Staging of Alzheimer’s Disease; MMSE, Mini Mental State Examination; NPI, Neuropsychiatric
Inventory; NT, no treatment; ROT, reality orientation therapy; TG, treatment group.

with MCI. overall, the article highlights the need for The National Institute for Health and Clinical Excel-
randomized controlled trials to evaluate the efficacy of lence in the uK, as well as numerous professional
cognitive intervention in MCI. societies in the fields of neurology and psychiatry,
studies have shown that cognitive intervention recommends that patients with mild-to-moderate AD
approaches in which patients with MCI acquire and apply should participate in cognitive stimulation programs.
learning strategies to optimizing ‘everyday’ memory per- The largest and most extensive randomized controlled
formance have beneficial effects.42,43 The results indicate trial to assess the use of cognitive intervention in AD
that patients with MCI can acquire and maintain know- used a global cognitive stimulating approach based on
ledge about memory strategies. Furthermore, by employ- reality orientation therapy.6,47 The aim of the study was
ing these strategies the patients can modify their everyday to determine whether presentation and repetition of
memory behavior. By including these strategies in their orientation information could increase cognition and
daily routines, patients affected by memory problems quality of life of patients with mild-to-moderate AD.
could potentially maintain their independence, an issue The results of this study revealed that participating in
that needs to be addressed in future research.42 cognitive stimulation therapy significantly enhanced the
global cognitive status and quality of life of the inter-
Alzheimer disease vention group when compared with the control group
A number of articles have reviewed the randomized (Table 2). A number-needed-to-treat analysis of the
controlled trials that were conducted to assess the use data indicated that cognitive therapy was as effective
of cognitive intervention in AD.6,38,44–46 In general, the as antidementia drugs (ChEIs) at relieving cognitive
studies found that specific cognitive intervention strat- symptoms—memory and orientation—associated with
egies could be clinically effective or practically benefi- AD and seemed to potentiate the beneficial cognitive
cial in patients with AD. Furthermore, a meta-analysis effects provided by ChEI treatment.44–46,48 Nevertheless,
designed to assess the use of cognitive interventions in long-term cognitive deterioration in patients with AD
AD provided evidence that restorative strategies seem cannot be stopped even with 2 years of pharmacological
to be more efficacious than compensatory strategies for and/or non-pharmacological treatment, but deterioration
alleviating memory deficits (Box 2).4 Global cognitive is greater and progresses faster in patients not receiving
stimulation was shown to be more efficacious at improv- any treatment at all.49 Results of two studies, one compar-
ing cognitive functioning in patients with AD than were ing stimulation of procedural memory with training of
cognitive interventions involving training of specific cog- partially spared cognitive functions,50 and one compar-
nitive functions.4 However, owing to the fact that substan- ing the effects of ‘recreational activities’ against a specific
tial methodical differences existed between the studies, cognitive program on global stimulation in patients with
these results should be interpreted with caution. AD,51 provide further support for the use of cog nitive

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intervention therapies in this condition. Immediate and Training seems to have three general effects on the
3–6 month follow-up assessments indicated that the cog- brain:55 it increases or decreases brain activity in speci-
nitive interventions significantly improved functional fic brain regions, and causes long-term global changes
competence in daily living in patients with AD, as well in brain activity when a specific task is being performed.
as alleviating caregiver distress. Global stimulation pro- Two possible scenarios could account for the changes
grams that aim to improve activities of daily living might in global brain activity that are associated with train-
be more beneficial to patients with AD than intervention ing: either specific regions of the brain that are activated
programs that stimulate specific cognitive functions. during the performance of a specific task before training
In summary, cognitive interventions can improve show altered levels of activity after training, or cognitive
global cognitive status, abilities of daily living and training causes additional cortical regions to be recruited
quality of life, and reduce behavioral disturbances, in after training. These changes in brain activity associated
patients with mild-to-moderate AD. The potential bene- with training reflect a qualitative shift—known as process
fits of cognitive stimulation have been demonstrated in switching—in the cognitive processes that underlie the
both patients with moderate-to-severe dementia,52 and performance of a given task.56 Thus, the cognitive pro-
patients with mild-to-moderate AD. Cognitive inter- cesses underpinning the performance of a task after train-
vention programs focusing on global cognitive stimu- ing are different from those used to complete the same
lation were found to be more effective at enhancing task before training. For example, brain activity could
cognitive and non-cognitive functioning than programs decrease in response to a particular stimulus when an
that trained specific cognitive functions.4 By contrast, individual becomes accustomed to, and better at, perceiv-
patients with MCI seem to benefit more from cognitive ing the information. At the cellular level, this net change
training than from global cognitive stimulation.32,53 in neuronal activity could reflect a minority of neurons
The findings mentioned above do not provide informa- being activated more strongly by the stimulus, and other
tion regarding the underlying biological mechanisms that neurons that were previously activated by the stimulus
are responsible for the improvements in global cognitive becoming unresponsive. Neural activity associated with
status. one study investigated the effects of cognitive– the performance of a cognitive task might also decrease as
motor intervention in patients with MCI or mild-to- a consequence of training, as the response time to perform
moderate AD, and found that participants with fewer the task decreases with practice and experience, meaning
years of formal education responded more strongly to that less neural processing is required to perform the
the cognitive intervention than patients deemed to have exercise. Furthermore, training and learning might alter
had more years of formal education.38 To explain this the level of awareness an individual requires to perform a
finding, the authors suggest that at a given level of clini- task, thereby altering the pattern of brain activity required
cal severity the underlying pathology is more advanced to accomplish the feat. Process switching might also evoke
in patients with AD with higher educational levels changes in task monitoring. For example, performing a
than in patients with lower educational levels. There- task might be challenging before training, but would
fore, the highly educated patients might be at the limit of become easier as the individual practices, thus requiring
their compensatory capacity and, thus, benefit less from less task monitoring—and fewer executive resources—for
cognitive interventions. This explanation is consistent the same level of performance after training.
with findings from another study, which reported that Decreased brain activity after training is observed in
although education delays the onset of cognitive decline, most studies of cognitive training, generally in paral-
once cognitive deficits become clinically apparent cog- lel to alterations to the neural processes underpinning
nitive decline is more rapid in individuals judged to be the performance of the task, as detailed in the previous
highly educated than in those with fewer years of formal paragraph. Functional MRI has shown decreases in brain
education.54 Better insights into how neuronal plasticity activity after training in the sternberg verbal task,57 in a
and cognitive reserve might affect the efficacy of cog- spatial working memory task,58 and in the n-back working
nitive intervention strategies in patients with cognitive memory task.59 A PET study of verbal recall also revealed
deficits could be provided by neuroimaging studies. reduced brain activity after training.60 In a further study
that examined the effects of training on completing a
Neuroimaging studies video game, researchers found that after a few weeks of
studies that have examined the neurobiological basis of practice, brain activity in the parietal cortex when playing
training programs have typically focused on examin- the game was decreased, and that decreased activity in
ing the effects of training on changes in brain activity in this brain region positively correlated with improved task
young, healthy individuals. These studies indicate that performance.61 This finding is consistent with the hypo-
training can alter brain function at the molecular and thesis that functional decreases in brain activity reflect
synaptic levels, as well as at the neural network level.7 more-efficient information processing in the brain.
Interestingly, these changes in neurobiological function Increased brain activity after training has been demon-
might underlie the increases in cognitive performance strated during the performance of cognitively taxing
that are associated with cognitive intervention strategies. tasks, such as playing musical instruments.62 In a study of
Both PET and functional MRI studies might further our working memory, increased activity in frontal and pari-
understanding of how brain activity changes in response etal cortices correlated with increased working memory
to cognitive intervention therapies. capacity after training.63

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As mentioned above, changes in brain activity after capacity to enhance or compensate for impaired cog-
training reflect parallel increases and decreases of acti- nitive functions seems to decline. Therefore, patients
vation in the neuronal network underlying the perfor- with MCI and patients with mild AD could benefit
mance of the task. In general, these changes probably differently from cognitive interventions. These initial
reflect decreases in the attentional demand required studies indicate that cognitive intervention can alter
by the task and increases in task-specific domains such neuronal function, and these functional changes can be
as memory. 64 Petersen and colleagues 64 argue that a measured with neuroimaging tools.
novel task requires high cognitive effort for successful
performance, and that training leads to a reduction in Implications for future studies
the cognitive activity required to successfully perform In general, most studies that have investigated the
this task. The increased brain activity associated with effects of cognitive interventions in AD and MCI have
performing a novel task is typically localized in brain involved relatively small numbers of patients and con-
areas associated with visual processing and memory.64 trols. Furthermore, owing to the wide range of cognitive
similar patterns of altered brain activity have also been interventions that have been implemented in these
observed in individuals who have successfully acquired a trials, comparisons of the data are problematic. Further
new motor skill.65,66 The key insight from these studies is studies with larger sample sizes are warranted to establish
that attentional processes are associated with decreases whether cognitive intervention programs can improve
in brain activity, whereas task-specific brain regions are and stabilize global cognitive functioning and delay
associated with increased brain activity after training. further disease progression.
only a few neuroimaging studies have investigated Most studies have failed to consider potentially con-
the effects of cognitive training or cognitive stimu- founding effects that could arise from the social inter-
lation in patients with AD. one of the earliest PET action with a trainer or instructor. Hence, the extent to
studies of patients with mild AD reported that a com- which the observed training benefits are actually due to
bination of cognitive training and phosphatidylserine cognitive intervention is unclear. Furthermore, studies
or pyritinol drug therapy was associated with increased investigating the effects of cognitive intervention in AD
brain glucose metabolism in temporal–parietal brain or MCI are typically relatively short in duration and,
areas during a continuous visual recognition task. 67 therefore, do not provide any information on the possible
Furthermore, patients receiving combined cognitive mid-term and long-term effects of this therapy on global
and drug therapies showed increased glucose metabo- cognitive functioning. Another issue worthy of investi-
lism and improved cognitive performance compared gation is whether cognitive intervention might delay
with control groups receiving either drug or cognitive the need for help and care dependency in the mid term
intervention alone.67 A PET study of elderly patients and long term. Finally, as the heterogeneous underlying
with memory impairments that investigated the effects causes of MCI and the various types of dementia could
of a 14 day mental exercise program in combination substantially affect the ability of cognitive interventions
with physical exercise, stress reduction and a healthy to provide benefits to patients with cognitive deficits,
diet showed that the inter vention substantially reduced better patient stratification is needed.36,69,70 Assessment
resting glucose metabolism in the dorsolateral pre- of neuropsychological status, multimodal biological
frontal cortex in the intervention group compared with markers,71 patterns of progressive regional brain atrophy,
the control group. The study participants receiving the and regional changes in brain metabolism72,73 will all aid
intervention were also shown to have increased verbal patient stratification and assist the development of cog-
fluency.68 The decreased resting glucose metabolism in nitive interventions that target patients with different
the dorsolateral prefrontal cortex might reflect increased levels of cognitive and global functioning.
cognitive efficiency, as no changes in brain glucose In summary, large, long-term (18–24 months in
metabolism were evident in the control group. duration) cognitive intervention studies that document
A randomized controlled trial has tested a 6 month information regarding the study participant’s neuro-
stage-specific cognitive intervention designed to increase psychological, neurogenetic and biomarker status are
cognitive and non-cognitive functions, which was required to establish whether cognitive intervention can
administered weekly in a group environment and com- positively affect global cognitive functioning in patients
pared with active control groups (v. Buschert, unpub- with MCI or AD.74 studies examining the neurobiologi-
lished work). In patients with amnestic MCI, greater cal effects of cognitive training in healthy individuals
cognitive bene fits were seen in those receiving the indicate that this intervention can substantially affect
intervention than in controls. Patients with mild AD also neural activity in brain areas associated with perfor-
benefitted from the intervention, but to a lesser degree mance of the cognitive function in question. We feel,
than those with amnestic MCI (s. Foerster, unpublished therefore, that future functional and anatomical studies
work). The gains in cognition were shown by PET to be should examine in detail how cognitive training influ-
associated with an attenuation in the decline in glucose ences the neural networks affected by the pathological
metabolism in cortical regions typically affected by AD. processes associated with both MCI and AD. In addi-
Cognitive reserve might be better preserved in patients tion, neuroimaging studies could identify which specific
with MCI who are at risk of developing dementia than neural networks in patients with MCI might respond
in patients with AD.14 As the disease progresses, the positively to cognitive training.75

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Recommendations for practice studies in MCI and AD could have important clinical
varying levels of cognitive functioning exist during implications. At present, however, no standardized,
the progression of AD, so matching appropriate cogni- replicable intervention programs have been designed for
tive interventions to patients with different cognitive the treatment of patients at different stages of AD.
and global functioning levels is desirable. Patients with Cognitive interventions that support global function-
advanced symptoms will receive fewer benefits from ing could delay the onset of AD by 5 years in patients
cognitive interventions that target specific cognitive who will eventually develop this condition. As a result,
functions than patients with preclinical or mild AD. the prevalence of AD could decrease by 50%, leading
By contrast, global cognitive stimulation and cognitive to substantial personal, social and economic benefits.
intervention strategies that aid performance of activities Compared with the pharmacological treatments cur-
of daily living might provide greater benefits to patients rently available for the treatment of AD—namely, ChEIs
with advanced AD. 52 A meaningful cognition-based and memantine—non-pharmacological cognitive inter-
intervention should focus on the distinct stages of the ventions have a number of advantages. With regard to
disease and aim to improve cognitive functions that health insurance costs, cognitive intervention programs,
increase the patient’s independence and autonomy. when administered in groups in the course of outpatient
Throughout the intervention, confrontation of indivi- treatment, seem to be highly attractive, as they are associ-
dual cognitive deficits should be avoided to prevent the ated with lower costs and higher cost-effectiveness than
participant from becoming disillusioned, which might have pharmacological treatments. 5 Furthermore, cognitive
a negative impact on the success of the therapy.68 Cognitive interventions are thought to cause no undesirable adverse
intervention places high demands on the therapist, and events, unlike antidementia drugs.
requires the application of current knowledge concerning The implementation of adequate intervention pro-
intervention techniques, content and strategy. grams for the treatment of AD requires the availability of
sufficient numbers of medical practitioners and specia-
Conclusions lists (and suitable institutions) to diagnose and treat all
Cognitive interventions have been shown to improve patients with this serious condition. Considering that the
global cognitive functioning and abilities of daily living, number of patients with dementia worldwide is expected
reduce behavioral disturbances, and have positive to increase dramatically from 35 million today to
effects on quality of life in patients with MCI or mild- 115 million in 2050,76 efforts to advance the development
to-moderate AD. Neuroimaging results indicate that and implementation of cognition-based interventions for
changes in attention underpin many of the improvements the treatment of AD must definitely be pursued.
in cognitive performance.
Evidence suggests that physical activity slows down cog- Review criteria
nitive decline and delays the onset of dementia in healthy PubMed was searched for articles published in English,
elderly adults. At present, however, the importance of with the following search terms: “cognitive training/”,
physical activity in the framework of non-pharmacological “cognitive stimulation”, “cognitive intervention”, “healthy
approaches to the treatment of AD remains unclear. elderly”, “mild cognitive impairment”, “Alzheimer’s
Given that patients with MCI have an increased risk disease”, “neuroimaging”, “DTI”, “SPECT”, “fMRI” and
of developing AD, and considering that no approved “PET”. In addition, we identified papers from references in
disease-modifying drugs are currently available for AD, the articles retrieved by the initial searches and selected
articles from our own archives.
the encouraging results from cognitive intervention

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