Cognitive Reserve and
Alzheimer Disease
Yaakov Stern, Alzheimer Dis.
Asso.c Disord. 2006, 20:
S69–S74.
Who has a higher risk of developing
Alzheimer’s Disease?

Higher IQ, education, occupational
attainment, or participation in leisure
activities
Brain Reserve
There does not seem to be a direct
relationship between the degree of brain
pathology or damage and the clinical
symptoms of that damage.
 Is there a reserve against brain damage?

Passive Model – Brain Reserve Capacity
Passive Models - Brain Reserve
Capacity (BRC) derives from brain size or
neuronal count.
 There may be individual differences in
BRC.
 There is a critical threshold of BRC: an
amount of brain damage sustained before
reaching a threshold for clinical
expression.

Cognitive Reserve (CR) Model
The cognitive reserve (CR) model
suggests that the brain actively attempts
to cope with brain damage by using
preexisting cognitive processing
approaches or by enlisting compensatory
approaches.
 Individuals with more CR would be more
successful at coping with the same
amount of brain damage.

CR – Neural Reserve
CR may be implemented in 2 forms:
neural reserve and neural compensation.
 Neural reserve - brain networks or
cognitive paradigms that are less
susceptible to disruption, perhaps because
they are more efficient or have greater
capacity.
 In healthy people – it is used when coping
with increased task demands.
 In brain pathology – it could help too…

CR- Neural compensation

Neural compensation - people suffering
from brain pathology use brain structures
or networks (and thus cognitive
strategies) not normally used by healthy
people to compensate for brain damage.
Models - Summary
The fact that one patient can maintain
more AD pathology than another but
appear similar clinically can be explained
by the CR models and not by the passive
models.
 However, it is likely that both CR concepts
are involved in providing reserve against
brain damage.

Measures of Reserve
Anatomic measures such as brain volume,
head circumference, synaptic count, or
dendritic branching are effective measures
of brain reserve.
 Many of these measures are influenced by
life experience and may change over the
lifetime.

Measures of Reserve

CR (cognitive reserve) is also influenced
by lifetime experience:



Measures of socioeconomic status, such as
income or occupational attainment.
Educational attainment including - number of
years of formal education, and degree of
literacy.
Measures of various cognitive functions, such
as IQ.
Measures of Reserve
Genetics + Exposure  innate intelligence
 Education
 Still, education, or other life experiences,
probably impart reserve over and above
that obtained from innate intelligence.
 CR is not fixed; at any point in one’s
lifetime it results from a combination of
exposures.

How does CR affect AD?
Experiences associated with more CR do
not directly affect brain reserve or the
development of AD pathology.
 Rather, CR allows some people to better
cope with the pathology and remain
clinically more intact for longer periods of
time.

How does CR affect AD?
Many of the factors associated with CR
may also have direct impact on the brain
itself. (ex.-IQ and brain volume).
 Environmental enrichment might prevent
or slow accumulation of AD pathology.
 Estimating CR :integrating the interactions
between genetics, environmental
influences on brain reserve and pathology,
and the ability to actively compensate for
the effects of pathology.

Epidemiologic Evidence for CR
Many studies have examined the relation
between CR variables and incident
dementia.
 Parallel studies have often examined the
relation between these variables and
cognitive decline in normal aging.

Education and CR
Several studies in India, England, and the
United States reported no association
between education and incident
dementia.
 However, lower incidence of dementia
in subjects with higher education has
been reported by at least 8 cohorts, in
France, Sweden, Finland, China, and the
United States.

Education and CR



Education has a role in age-related
cognitive decline.
Several studies of normal aging reporting
slower cognitive and functional decline in
individuals with higher educational
attainment.
The same education related factors that
delay the onset of dementia also allow
individuals to cope more effectively with
brain changes encountered in normal
aging.
Occupation and CR
No or vague association between
occupation and incident AD was found.
 Nevertheless, several studies have noted
a relationship between occupational
attainment and incident dementia.
 As mentioned above, occupational
attainment was often noted to interact
with educational attainment.

Social Status and CR
Germany - only poor quality living
accommodations were associated with
increased risk of incident dementia.
 Indicators of social isolation such as low
frequency of social contacts within and
outside the family circle, low standard of
social support and living in single person
household did not prove to be significant.

Leisure Activities and CR

Activities associated with lower risk of
incident dementia:





Traveling, doing odd jobs, knitting
Community activities, gardening
Having an extensive social network, participating in
mental, social, and productive activities
Intellectual activities (reading, playing games,
going to classes)
Leisure activities (reading, playing board games or
musical instruments, and dancing)
Life Expectancy and CR

In a prospective study of AD patients
matched for clinical severity at baseline,54
patients with greater education or
occupational attainment died sooner than
those with less attainment.

Does this contradict the CR hypothesis?
Life Expectancy and CR
At any level of clinical severity, the
pathology of AD is more advanced in
patients with CR.
 At some point, the greater degree of
pathology in the high reserve patients
would result in more rapid death.

Imaging Studies – resting CBF



Several imaging studies of CR in AD used resting
cerebral blood flow (CBF).
These studies have found negative correlations
between resting CBF and years of education,
premorbid IQ, occupation and leisure.
The negative correlations are consistent with the
CR hypothesis’ prediction that at any given level
of disease clinical severity a subject with a higher
level of CR should have greater AD pathology (ie,
lower CBF).
Imaging Studies – resting CBF
Alexander GE, Furey ML, Grady CL, et al. Association of
premorbid function with cerebral metabolism in
Alzheimer’s disease: implications for the reserve
hypothesis. Am J Psychiatr. 1997;154:
165–172.
Imaging Studies – resting CBF
Stern Y, Alexander GE, Prohovnik I, et al. Relationship between lifetime occupation and
parietal flow: implications for a reserve against Alzheimer’s disease pathology. Neurology.
1995;45:55–60.
Imaging Studies – Neuropathologic

A neuropathologic
analysis showed
that for the same
degree of brain
pathology there
was better
cognitive function
with each year of
education.
Bennett DA, Wilson RS, Schneider JA, et al. Education modifies
the relation of AD pathology to level of cognitive function in
older persons. Neurology. 2003;60:1909–1915.
Functional Imaging of CR
Functional imaging studies should be able
to capture the differences in how tasks are
processed due to CR.
 One approach - to identify patterns of
task-related activation that differ between
AD patients and controls, and to
determine whether they are
compensatory.

PET and verbal recognition
H215O PET was used to measure regional
CBF in patients and healthy elders during
a verbal recognition task.
 Task difficulty was adjusted so that each
subject’s recognition accuracy was 75%.
 In addition, CBF was measured for
different study list size.

PET and verbal recognition

In healthy elders and 3 AD patients, a
network of brain areas was activated
during performance:
Left anterior cingulate



Left anterior cingulate
Anterior insula
Left basal ganglia
anterior insula
Basal ganglia
Higher study list size -> increased
recruitment of the network
 Individuals who are able to activate this
network to a greater degree may have
more reserve against brain damage.

PET and verbal recognition

The remaining 11 AD patients recruited a
different network:




Temporal cortex
Calcarine cortex
Posterior cingulate
Vermis.
vermis
temporal
calcarine
Posterior
cingulate
Stern Y, Moeller JR, Anderson KE, et al. Different brain networks mediate task performance in normal
aging and AD: defining compensation. Neurology. 2000;55:1291–1297.
PET and verbal recognition
Higher study list size -> increased
activation of this network.
 Neural compensation - This alternate
network may be used by the AD patients
to compensate for the effects of AD
pathology.

Neural Compensation
Is this alternate network associated with
better performance?
 In several studies, some elders showed
additional activation in areas contralateral
to those activated by younger subjects.
 The elders who showed this additional
activation performed better than those
who did not, indicating that it was
compensatory.

PET and Nonverbal Tasks
A PET study identified brain areas whose
activation during performance of a
nonverbal memory task correlated with an
index of CR calculated from measures of
education and literacy.
 Such areas were identified in both healthy
controls and patients with AD, suggesting
that these areas may reflect the neural
instantiation of CR.

PET and Nonverbal Tasks
Scarmeas N, Zarahn E, Anderson KE, et al. Cognitive
reserve mediated modulation of positron emission
tomographic activations during memory tasks in
Alzheimer disease. Arch Neurol. 2004;61: 73–78.
PET and Nonverbal Tasks

Some brain areas showed:


Increased activation as a function of increased
CR in the elderly controls
Decreased activation in the AD patients.
Higher CR -> higher adaptive activation:
Compensation for the effects of AD
pathology in the AD patients
 This is consistent with our definition of
neural compensation.

Summary
In summary, the imaging evidence is
beginning to provide support for the 2
hypothesized neural mechanisms
underlying CR:
 Neural reserve which emphasizes
preexisting differences in neural efficiency
or capacity.
 Neural compensation, which reflects
individual differences in the ability to
develop new, compensatory responses to
the disabling effects of pathology.

Conclusions
Clinical observation of mild cognitive
impairment may be accompanied by very
minimal pathology or more than enough
to meet pathologic criteria for AD.
 A proportion of this variability may be
explained by CR.
 Measuring CR therefore becomes an
important component of the diagnostic
process.

Conclusions
Clinical evaluation alone is an insufficient
measure of a patient’s true status.
 Indexes of pathology:





Biomarkers
Imaging AD pathology itself
Imaging the effect of pathology on resting
metabolism in entire brain
Imaging the effect of pathology on particularly
vulnerable brain area.
Conclusions
There is a need for measuring individual’s
CR - the ability to cope with pathology.
 CR may be evaluated using educational and
occupational attainment and quantified
using functional imaging.
 The combination of clinical characterization,
measures of underlying pathology and
indices of CR would provide a more
complete picture of a patient’s status.
 Important for: early diagnosis, determine
prognoses and progression over time.

Conclusions
Finally, the fact that different life
exposures including education, occupation
and leisure, impart reserve against AD in
epidemiologic studies raises the possibility
that an individual’s CR could be increased
through some set of systematic exposures
or interventions.
 This would result in a nonpharmacologic
approach for reducing risk of developing
AD.
