Esiri and Chance Alzheimers Research & Therapy 2012, 4:7

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REVIEW

Cognitive reserve, cortical plasticity and resistance

to Alzheimers disease
Margaret M Esiri*1,2 and Steven A Chance1

Introduction
Abstract The early 21st century confronts us with a dual dilemma
There are aspects of the ageing brain and cognition concerning old age: rst, there is going to be an enormous
that remain poorly understood despite intensive efforts increase in the number of elderly people, and second,
to understand how they are related. Cognitive reserve there is at present very little that can be oered to help
is the concept that has been developed to explain those many people who become demented. The best way
how it is that some elderly people with extensive to confront these twin diculties must be to maximise
neuropathology associated with dementia show little the chances of elderly people avoiding cognitive decline
in the way of cognitive decline. Cognitive reserve is and dementia. But how is this to be done?
intimately related to cortical plasticity but this also, We know that advancing age is by far the largest risk
as it relates to ageing, remains poorly understood factor for developing sporadic dementia but we also
at the present time. Despite the shortcomings in know that there is a wide range of cognitive performance
understanding, we do have some knowledge on in old age. What attributes determine the cognitive fate
which to base efforts to minimise the likelihood of of individual elderly people? Here we review what is
an elderly person developing dementia. For some known about this important subject.
risks the evidence is far from secure, but resistance to
Alzheimers disease (AD) appears from epidemiological The concept of cognitive reserve
studies to be contributed to by avoiding hypertension The brain undergoes changes in structure, metabolism
in middle life, obesity, depression, smoking and and function as it ages [1,2]. While some of these changes
diabetes and head injury and by undertaking extended are apparent on examining the brain of an elderly person,
years of education, physical exercise, and social and whether by imaging when they are alive or by post-
intellectual pursuits in middle and late life. Nutritional mortem examination, others are not. Some of the changes
factors may also promote healthy brain ageing. are well established as relating to cognitive decline and
Resistance to AD is also contributed to by genetic dementia, most notably the pathological features of
factors, particularly apolipoprotein E2, but some Alzheimers disease (AD), but also cerebrovascular
combinations of other genetic polymorphisms as well. disease and alpha synuclein pathology. Yet it has become
Although multiple factors and possible interventions clear from unselected epidemiological studies linked to
may influence cognitive reserve and susceptibility neuropathology that there is not infrequently a mis-
to dementia, much more work is required on the match between pathological changes found post-mortem
mechanisms of action in order to determine which, and the recorded cognitive performance of a person
if any, may improve the clinical and epidemiological before they died [3]. In some cases cognitive performance
picture. Understanding of how such factors operate is below the level expected for the amount of pathology
may lead to new initiatives to keep the elderly found but more frequently someone with a substantial
population in the 21st century able to lead active and load of pathology had nonetheless performed cognitively
fulfilling lives. within the normal range before death. A recent large
study found that careful quantication of neuropathology
and brain weight accounted for only between a third and
a half of the variance in cognitive performance in a
*Correspondence: Margaret.esiri@clneuro.ox.ac.uk
relatively unselected group of elderly people, leaving the
2
Department of Neuropathology, Oxford Radcliffe NHS Trust, Oxford OX3 9DU, UK rest unaccounted for [4]. Cognitive reserve is the concept
Full list of author information is available at the end of the article that has been developed to deal with this discrepancy [5].
Potential issues of measurement error arise when
2010 BioMed Central Ltd 2012 BioMed Central Ltd considering the concept of cerebral reserve relating to
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ceiling and oor eects in testing instruments but, in cerebral architecture that is presumably the basis for
general terms, most investigators attribute at least some ongoing cognitive function. It is notable that most assess-
cognitive reserve to having a well developed and nourished ments of cognitive decit are in fact measures of
brain with an abundance of synapses and healthy neurons remaining function (that is, reduced measures of positive
in those parts of the brain that are concerned with ability). Therefore, assessing the degeneration of intact
cognition - mainly association cortex, hippocampus and structure is as important as the accumulation of patho-
the parts of the brain that these are connected to. This logy. Synapse loss [10] and minicolumn change [9] have
hypothesised basis for cognitive reserve ts quite well shown some of the clearest structural relationships with
with the fact that longer years of education protect functional decits in ageing and dementia. In the context
against dementia and, conversely, with the enhanced risk of identifying a neural basis for cognitive reserve, patho-
of dementia experienced by those who have had a serious logical markers may be identied with decit, whereas
head injury. This concept particularly links cognitive measures of intact architecture should correspond to
reserve to grey matter regions of the brain and to the reserve.
cortical plasticity inherent in these. However, there are
also changes in the white matter of the brain that are Structural changes
increasingly recognised with ageing, and some of these At the large scale, total brain size contributes signicantly
are not readily explained as secondary to the grey matter to the variance in cognitive ability between individuals
changes. Thus, we need to consider the evidence for both [4]. Total brain shrinkage typically occurs with ageing in
grey and white matter contributions to cognitive reserve. humans, which a recent report suggests may be unusual
compared to other primates who do not show this
Grey matter, cortical plasticity and cognitive reduction [11]. In a longitudinal MRI study of twins in
reserve adulthood, progressive thinning of the frontal cortex and
Not all forms of reserve are the same, and they depend on thickening of the medial temporal cortex is heritable and
the forms of brain insult and neuroplasticity that may be related to cognitive ability (IQ) [12]. (IQ measures are
involved. Stern [6] has compared neural compensation, taken to be a good indicator of premorbid cognitive
neural reserve, and cognitive reserve. Neural compensa- reserve [13].) Genes inuencing variability in both intelli-
tion and neural reserve are characterised as task- gence and brain plasticity partly drive these regional
dependent in contrast to more generalised cognitive associations. In particular, training in alternative problem
reserve. Compensation is a response to pathologically solving strategies likely to be associated with prefrontal
altered processing, whereas reserve refers to dierences cortex (PFC) function has been linked to enhancement of
in task-related processing without pathology. Stern cognitive reserve. Our own data have found a closer
considers all three to be neural mechanisms in the sense relationship between cognitive function and micro-
that they are attributed to interactions within neural anatomical measures in association cortex than with total
networks. However, the relationship between cognitive brain size [9] (see below).
reserve and its architectural neural basis is not clear. Part Older adults are capable of counteracting age-related
of the explanation for the large proportion of variance neural decline through plastic reorganization of neuro-
that remains unexplained in the study by Dowling and cognitive networks. At the small scale, on the structural
colleagues [4] is that neuropathological measures are un- level, several aspects of neuroplasticity occur in adult
likely to account fully for cognitive ability. Reed and brains, including alterations of dendritic arborisation,
colleagues [7] have used the mis-match between patho- synaptic remodelling, axonal sprouting, neurite exten-
logy and cognitive performance as an index of neural sion, synaptogenesis, and neurogenesis [14]. The hippo-
reserve. This measure merges the neuropsychological campus is a region of high neuroplasticity, with ongoing
domain and the neuropathological domain. However, myelination and neurogenesis during adulthood [15,16].
such a measure depends on the presence of pathology The PFC is also a dynamic structure, capable of a neuro-
and therefore does not oer insight into the potential plastic response to changes or damage with an extended
reserve that exists prior to the onset of pathology. As an period of development during childhood and adoles-
alternative, an appropriate measurement of intact archi- cence, and a decline in adulthood in humans [17].
tecture should provide a neuroanatomical index that The neuroplasticity hypothesis therefore oers a mecha-
precedes pathology, changes with normal ageing, and nism to help explain dierential regional vulnerability in
correlates with cognitive ability [8]. AD [18,19]. It suggests that dierences in disease
In previous work [9] we have drawn attention to a progression are due to dierent intrinsic rates of
distinction in the neuroanatomical domain - between the neuropathological change, related to regional dierences
markers of neuropathological processes, such as plaques in neuroplasticity. Ageing makes neurons work harder to
and tangles, and measurement of the remaining, intact meet neuroplastic demands. A model incorporating
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intrinsic vulnerability (for example, [14]) therefore oers cognitive reserve may be associated with neural resis-
a link to normal aging. Grafman and Litvan [20] have tance to the spread of pathology.
identied four major forms of neuroplasticity: map One possibility is that dierent regional connectivity
expansion (mainly due to skill learning), cross-modal contributes to dierent plastic demands and dierent
reassignment (by rewiring following injury), homologous aspects of cognitive reserve. For example, the serial
area adaptation (the shift of function, often to the oppo- connections of the entorhinal-hippocampal pathway are
site hemisphere, due to injury in early life), and compen- more constrained than the diverse connections of the
satory masquerade (an alternative processing strategy for polymodal prefrontal cortex, reducing the options for
a task). These forms of neuroplasticity tend to be responses neural compensation. One consequence may be the
to specic events or tasks. However, there is also requirement for sustained adult neurogenesis in the
evidence of an over-arching trajectory of change in hippocampal region while the preservation of white
structure across the lifespan [21], to which the contribu- matter connectivity may be relatively more important in
tion of these event-driven forms of plasticity is uncertain. the PFC.
Rosenzweig [22] has reviewed the range of mechanisms
of neuroplasticity across the lifespan, and Gopnik [23] White matter and cognitive reserve
describes a contrast in learning strategies and plasticity White matter atrophy was highlighted in 1989 when, in a
in childhood compared to adulthood. It is the latter stage quantitative neuropathological study of elderly brains, it
of persistent adult neuroplasticity that is likely to be most was found that people without cognitive decline but with
relevant for determining the eects of age and dementia some AD pathology had atrophy of white matter but not
on cognitive reserve (although see Stem cells and of grey matter, whereas those with dementia and more
neurogenesis section below). extensive AD pathology had both grey and white matter
Age-related dendritic growth reects hierarchical atrophy. It was suggested that white matter atrophy may
organisation between cortical regions [24], with greater precede whole brain atrophy in ageing brains [27].
growth in limbic and association cortex where there is Neuroimaging has taken this concept further.
greater arborisation contrasted with stability or regres- OSullivan and colleagues [28] described reduced diu-
sion in less complex primary cortex [25]. Regional dier- sional anisotropy, a measure of white matter integrity,
ences in the width of minicolumns (the radial columns of and higher mean diusivity in elderly people with normal
cells that constitute the cerebral cortex) also reect this cognitive performance for age compared with young
hierarchy [19]. The minicolumns become thinner with control subjects. Another early diusion tensor imaging
age [24] and we have shown that the relationship between study identied reduced white matter integrity in the
minicolumns and cognitive function in association cortex splenium of the corpus callosum, superior longitudinal
is independent of general brain atrophy [8]. Furthermore, fasciculus, and cingulum whereas the pyramidal tracts
in AD, a higher density of tangles occurs in the more were spared [29]. Bartzokis and colleagues [30] found,
plastic regions and is correlated with the degree of using the transverse relaxation rate, that people who were
minicolumn disruption [26]. ApoE4-positive, and therefore at increased risk to
Not all regions associated with extended plasticity in develop AD (though they performed cognitively normally
adulthood are early casualties in AD; for example, dorso- when examined), had a reduced cognitive processing
lateral PFC is aected later. The expression of plasticity as speed, which was signicantly correlated with myelin
a risk factor may be compensated by the availability of breakdown in late myelinating white matter regions.
neural reserve. A study of the dorsolateral PFC found Presymptomatic carriers of familial AD mutations have
that the microstructure changed with normal ageing and altered diusion tensor imaging signal in white matter
that minicolumn thinning and accumulating plaque load throughout the brain and particularly in the perforant
mirrored the decline in IQ [8]. The role of the PFC in pathways, the fornix, and orbito-frontal white matter
cognitive reserve indicates that the thinning of mini- [31]. It was suggested that the changes in the fornix in
columns in the PFC may reect the loss of the initial particular may provide a biomarker for early disease in
neural reserve (for example, loss of neuropil and neuronal sporadic AD.
connections) in early aging. We also found that AD Andrews-Hanna and colleagues [32] used functional
patients with a high IQ were older at time of death MRI signal correlations between regions within large-
compared to patients with a low IQ score and the density scale brain systems in young and old cognitively normal
of tangles was less in the patients with high IQ. The subjects (mean Mini-Mental State Examination in the
implication is that individuals with greater reserve tend elderly score of 28.8) and showed marked reductions
to develop dementia later in life. Moreover, the low with age in normally present functional correlations
density of tangles with high IQ raises the possibility that, within two higher order brain systems. The worst aected
in addition to neural reserve and neural compensation, system was the anterior to posterior components within
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the default network. Reduced correlations were asso- half of cases of AD might be attributable to such factors:
ciated with loss of white matter integrity. diabetes, midlife hypertension, midlife obesity, smoking,
Abnormalities in the default mode network were also depression, cognitive inactivity or low educational attain-
detected using resting state paradigms in mild cognitively ment and physical activity [37]. These factors are derived
impaired subjects [33]. The level of deactivation diered mainly from epidemiological studies and not from
in the anterior frontal, precuneus and posterior cingulate interventional studies, which at present remain inade-
in AD when compared to controls, and the level of quate [38]. These can be classied according to whether
deactivation was intermediate in mild cognitive impair- they are thought to act by strengthening brain reserve
ment. Both studies suggest activity in the default mode before it is assaulted by the eects of age on the one hand
network may provide a marker for early changes and and those that constitute a reaction to such assaults on
indicate continuity between normal ageing and so-called the other. It is beyond the scope of this review to examine
pathological ageing. these factors in detail but we shall give them brief
The pathological basis of this purported white matter consideration here.
deterioration with ageing, which occurs in the absence of
overt white matter changes such as hyperintensity on T2 Psychosocial factors
imaging, is not well delineated, but Bartzokis [34] has The important factors here are avoidance of depression,
suggested that dysfunction of oligodendrocytes and the itself seemingly partly dependent on healthy maternal
myelin sheaths they maintain may be to blame. inuences on the fetus, or, more realistically, prompt
recognition and treatment of depression; extended years
Resistance to Alzheimers disease and quality of education, captured by tests of reading
This review has so far considered mainly changes that ability; and abundant leisure, exercise and cognitive
occur in the brain with normal ageing. Although there activities in middle and early old age [7,37,39]. A broad
are some investigators who prefer to consider AD as category of cognitive enrichment includes physical,
distinct from ageing, we believe that there may be more mental, and social activities that may improve adult
advantages in regarding it as part of the spectrum of cognitive function [40]. Clare and colleagues [41] have
change that occurs in the brain with age. This approach is identied three categories of intervention: cognitive
borne out by the enhanced associations that have been stimulation involves non-targeted procedures to enhance
found of pathology with AD genetic susceptibility alleles general mental function, cognitive training involves
if analyses involve not only neuropathological cases of theory-driven intervention, and cognitive rehabilitation
denite AD but also other elderly cases with less marked tackles impairments resulting from neuropsychiatric
AD pathology, referred to in the study by Bennett and disorders. In normal ageing, engagement in daily arith-
colleagues [35] as intermediate phenotypes. This was metic puzzles has been shown to improve function in a
also the approach to linking neuropathological variables randomized controlled trial [42]. How behavioural and
and a range of cognitive scores in elderly subjects that psychosocial enrichment strategies might interact with
was taken by Dowling and colleagues [4]. There are so psychopharmacological enhancement in healthy subjects
many changes that are seen to a severe degree in denite is unclear, but it seems reasonable to hypothesise that it
AD and to a milder degree in normal ageing that this strengthens cognitive reserve. Rozzini and colleagues
intermediate phenotype model seems to make eminent [43] found enduring improvement in mild cognitive
sense. These include evidence in the brain of oxidative impairment patients receiving combined pharmaco-
and other free radical damage, reduced anti-oxidative logical therapy and cognitive training in a one-year
capacity, loss of synapses, expression of cell division cycle randomized study (although subjects receiving only
markers and neurons displaying hyperploidy, to name pharmacological intervention also improved). However,
but a few. It is acknowledged that there may be step-wise it has been suggested that cognitive training is of limited
blips within a spectrum of age-related changes encom- benet in demented subjects [41].
passing AD that may inuence cognitive performance
and be marked by particular pathological changes, as Vascular risk factors
suggested by Herrup [36]. Nevertheless, in the rest of this Vascular risk factors seem, from epidemiological studies,
review, in which we consider what may constitute resis- to operate particularly at the middle stages of life. Hyper-
tance to AD, we shall follow this intermediate pheno- tension, in particular, needs to be avoided and other risk
type approach and include resistance to brain ageing. factors for AD that probably act through an eect on
Factors that may protect an individual from progressing vascular risk also need to be avoided: smoking, obesity
to the AD end of the spectrum of possible change as they and diabetes. Diet, which also feeds into the risks of
age are legion. A recent review considered seven obesity and vascular disease, may also be protective if it
modiable risk factors for AD and calculated that up to avoids much saturated fat and is rich in sources of
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vitamins, omega-3 fatty acids and anti-oxidants (for results. Avoidance of head injury may be protective
example, curcumin). There is some evidence that against AD at least in part because head injury is a cause
vitamins B12, folate and B6 are protective (by reducing of brain inammation, although there may be a more
blood homocysteine levels) [44], as is resveratrol in red direct link between head injury and amyloid plaque
wine. While epidemiological evidence for these protec- formation [52]. Inammation may be inuenced by
tive factors is quite strong, evidence that adopting them systemic and local infections. For example, latent herpes
is eective in preventing AD is less sound or even simplex infection of the brain is one of several infections
negative, probably because they have been applied in that have been suggested to inuence risk of AD [53].
trials too late in the course of the disease and for too
short a period of time. These factors likely operate by Cellular mechanisms in the brain
preventing brain pathology. Cortical and hippocampal neurons are critical elements
There are several putative mechanisms through which that need protection in old age and as a part of the
such dietary factors may act. Taking omega-3 fatty acids resistance to AD. Neurons dependency on oxidative meta-
as an example, docosahexaenoic acid (DHA) is the main bolism is a source of danger as mitochondria become less
omega-3 fatty acid in the brain and an essential ecient with age as a consequence of their generation of
component of synaptic membrane phospholipids, and free radicals, which then damage the mitochondria
consequently may play a role in synaptic remodelling themselves as well as other cellular constituents. The
[45]. DHA attenuates amyloid- secretion, an eect enormous cell surface area that requires constant main-
accompanied by neuroprotectin D1 formation, which tenance is also an Achilles heel for many neurons as it
promotes brain cell survival [46]; DHA also protects increases the need for energy, which, in turn, is dependent
from dendritic pathology in an AD mouse model [47]. on mitochrondrial function. A third source of diculty in
Furthermore, another omega-3 fatty acid, eicosahexaenoic maintaining healthy neurons in old age is their vulnera-
acid, is an anti-inammatory precursor. Consequently, bility to excitotoxic damage mediated through excess
omega-3 fatty acids are involved in gene expression stimulation of glutamate receptors. To defend themselves
dierences, synaptic plasticity and dendritic structural against free radical damage, cells require eective anti-
changes that plausibly contribute to cognitive reserve. oxidant mechanisms, with which neurons are not overly
Evidence for an eect of hormones on AD risk is endowed. Some of the dietary and lifestyle habits that
controversial but increasing. Thus, testosterone acts as a protect against AD probably operate through boosting
protective factor in men [48] and oestrogen replacement anti-oxidant mechanisms either directly or indirectly.
therapy may be protective if administered initially at or Glial cells also play important protective roles. Astro-
shortly after the menopause (but not later) in women cytes are known for their neuroprotective properties,
[49]. Raised cortisol levels are thought to represent a risk such as release of growth factors, control of potentially
factor for AD and therefore need to be avoided by neurotoxic transmitters and promotion of neuroprotec-
limiting stress. Raised cortisol levels may explain, at least tive eects of oestrogens [54,55], although they have
in part, the manner in which depression promotes AD. recently been shown in co-cultures of neurons and astro-
There is good evidence that physical activity both in old cytes to be critically involved in the toxicity that beta-
age and earlier in life protects against AD. It may do this amyloid has for neurons [56]. Microglia may have altered
in part by protecting against vascular risk factors such as properties in the ageing brain that enhance their ability to
hypertension, obesity and diabetes, but it also appears to exert neurotoxic eects [57,58].
protect the brain more directly by promoting growth As reviewed by Iadecola [59], brain endothelial cells
factor production and neurogenesis (see below). have critical roles to play in the ne tuning of oxygen and
Much has been written about the importance of metabolite supply from the blood to the brain in response
systemic and brain inammation in inuencing AD risk. to neural activity and in enabling waste products of such
The pathology of AD includes enhanced activation of activity to be removed. They also exert a protective eect
microglial cells, and the remarkable ability of macro- on nerve cells by producing growth factors such as brain-
phages to eliminate beta amyloid from the brain in derived neurotrophic factor. These endothelial cells are
experimental AD drew attention to the power of these subjected to oxidative damage and toxic eects of beta-
cells to inuence pathological events in this disease [50]. amyloid produced in the brain, which can compromise
There is some epidemiological evidence that chronic these functions during ageing and promote endothelial
inammatory diseases such as rheumatoid arthritis and cell autophagy. In transgenic AD in mice there are
leprosy, requiring long-term treatment with anti-inam- changes in cerebral blood ow regulation long before
matory agents, are protective against AD [51] but there is evidence of beta-amyloid deposition in the brain,
attempts to treat AD or mild cognitive impairment with suggesting that vascular changes occur at a very early
anti-inammatory therapy have had disappointing stage in the pathogenesis of genetically determined AD.
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Table 1. Some protective genetic effects against Alzheimers disease

Control allelic Control combination Odds ratio of
Gene(s) SNP(s) frequency frequency AD (95% CI)
Effects attributable to single genetic loci
CLU rs1113600AvsG A:40% 0.88 (0.86-0.90)a
PICALM rs3851179AvsG A:36% 0.88 (0.86-0.90)a
CD33 rs3865444VvsC A:32% 0.89 (0.86-0.92)a
Effects attributable to two-locus combinations
APOE rs429358/rs7412 9.1% 0.44 (0.39-0.50)b
2 vs others
PPARA, IL1A rs4253766/rs378550 11.4% 0.71 (0.57-0.90)b,c
(TC+TT)/(CA+CC) vs others
PPARA, IL1B rs1800206/rs16944 11.6% 0.74(0.60-0.92)b,c
(GC+GG)/(GA+GG) vs others
a
Data from the AlzGene (Caucasians) [72]. bData from Farrer and colleagues (APOE) [73], the Epistasis Project (PPARA, IL1A, IL1B; all Caucasians). cControlling for age,
sex and APOE4. AD, Alzheimers disease; APOE, apolipoprotein E; CD33, CD33 antigen; CI, confidence interval; CLU, clusterin; IL1A, interleukin-1; IL1B, interleukin-1;
PICALM, phosphatidyl inositol-binding clathrin assembly protein; PPARA, peroxisome proliferator-activated receptor-. Data in Table 1 are courtesy of DJ Lehmann.

Stem cells and neurogenesis The potential role of neurogenesis in cognitive reserve
In animal experiments, both voluntary exercise and and its manipulation in old age has received considerable
environmental enrichment stimulate adult hippocampal attention [66], although much is yet unknown regarding
neurogenesis. Running can in part reverse the decrease possible intervention in humans. The indication of
in neurogenesis observed in aged animals and improves neurogenesis in association cortex but not in a primary
learning in aged animals [60]. Sequentially combining the sensory area (striate cortex) in monkeys [67] hints at
eects of physical activity with environmental enrich- more widespread neurogenesis reecting some of the
ment has been shown to have an additive eect on the brain region hierarchical dierences already mentioned.
number of new neurons in the dentate gyrus [61]. However, the generality of ongoing neurogenesis in
Kempermann and colleagues [62] have proposed that higher neocortical regions is uncertain (for example,
continued physical and mental activity maintains a [68]), especially in humans.
neurogenic reserve of potential neurons that may be
integrated into the hippocampal network. However, the Genes
number of precursor cells that may be recruited is limited Genes are thought to have a major impact on AD risk and
by the proliferative cells, whose survival may depend on probably many of the psychosocial and lifestyle factors
activity in early life. This links later life reserve to activity mentioned above exert their eects by altering the
in early life and indicates that early life behaviour can epigenetic control of gene expression [69]. Although the
only be partly compensated later. The interaction is gene encoding apolipoprotein E is most well established
reminiscent of Hebbs original nding that early experi- as inuencing risk of late onset AD, several other gene
ence inuences problem-solving ability in maturity [63]. polymorphisms have also emerged from recent studies as
New cells in the hippocampus initially express increased having a modest eect on AD risk (Table 1).
synaptic plasticity and it has been claimed that all long- Combinations of gene polymorphisms appear to have a
term potentiation in the dentate gyrus originates from stronger inuence than single gene eects.
new cells; meanwhile, long-term potentiation has been SIRT1 is a gene that profoundly inuences life span in
shown to induce adult hippocampal neurogenesis in vivo rodents and is activated by calorie restriction, an
[62]. Of additional interest, considering that therapeutic intervention that has long been recognised as extending
neuropharmacology for AD has predominantly targeted the lifespan of rodents by 50% or more. SIRT1 codes for
the cholinergic neurotransmitter system, cholinergic an acetylase that counteracts the eects of stress on cells.
input from the medial septal area promotes precursor Overexpression of SIRT1 in AD transgenic mice reduced
cell proliferation in the dentate gyrus [64]. Environmental beta-amyloid production, inammation, tau phosphory-
enrichment also leads to increased cortical acetyl- lation and improved learning [70]. A substance in red
cholinesterase activity [65], although the clinical manipu- wine, resveratrol, has SIRT1-activating eects. Another
lation of acetylcholine levels in dementia has met with signalling pathway that inuences life span and
limited success. experimental expression of AD transgenes is the target of
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Abbreviations
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AD, Alzheimers disease; DHA, docosahexaenoic acid; MRI, magnetic
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Competing interests
20. Grafman J, Litvan I: Evidence for four forms of neuroplasticity. In Neuronal
The authors declare that they have no competing interests.
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