Noradrenaline, Cognitive Reserve and Alzheimer’s Disease: A
Hypothesis
Ian H Robertson
Trinity College Institute of Neuroscience and School of Psychology
Trinity College
Dublin 2
Ireland
Address for correspondence:
Institute of Neuroscience
Lloyd Building
Trinity College
Dublin 2
Ireland
Tel: +35318962684
Fax: +35318963183
Email iroberts@tcd.ie
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Abstract
The gap between symptoms and pathology in Alzheimer’s Disease has been explained
by the hypothetical construct of ‘cognitive reserve’ – a set of variables including
education, intelligence and mental stimulation which putatively allow the brain to
adapt
to – and hence mask - underlying pathologies by maintaining cognitive
function in spite of underlying neural changes. This review proposes a hypothesis that
a biological mechanism may mediate between these social/psychological processes on
the one hand, and apparently reduced risk of Alzheimer’s Disease on the other,
namely repeated activation of the noradrenergic system over a lifetime by the
processes implicated in cognitive reserve. Noradrenaline’s neuroprotective effects
both in vivo and in vitro, and its key role in mediating the neuroprotective effects of
environmental enrichment on the brain, make NA’s key role in mediating cognitive
reserve - by disease compensation, disease modification or a combination of both - a
viable hypothesis.
Key Words
Alzheimer’s Disease; Cognitive Reserve; Cognition; Aging; Noradrenaline; Locus
Coeruleus; Environmental Enrichment.
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1. The cognition-pathology gap in Alzheimer’s Disease
One of the major obstacles to developing effective treatments or preventions for
Alzheimer’s Disease (AD) is the imperfect correlation between biological measures
of pathology in the brain on the one hand – amyloid plaques, neurofibrillary tangles,
PET-measured cerebral perfusion or volumetric MRI for instance - and measured
cognitive function and real life performance on the other (McKhann, Knopman et al.
2011). In the famous ‘nun study’ for instance (Riley, Snowdon et al. 2002), no less
than 32% of elderly participants with Braak Stage III and IV pathology (out of a
maximum of 6 stages determined post-mortem) had normal memory function before
death. Furthermore, while there was a modest but significant correlation of 0.57
between autopsy-determined pathology and general cognition among individuals who
had some memory impairment, there was no significant relationship between
pathology and global cognition in those with intact memory function, in spite of the
existence of other types of other cognitive impairment in many of this latter group.
A common explanation for this cognition-pathology discrepancy is that cognition and
memory function are maintained at relatively high levels in spite of the developing
underlying pathology, of which the presence of amyloid plaques may be one
important disease-specific marker; this may happen because of compensatory
adjustments made by the brain which help it reorganize to maintain function in spite
of the developing pathology (Dubois, Feldman et al. 2010; McKhann, Knopman et al.
2011). The development of a human amyloid marker in the form of amyloid PET
scanning with Pittsburgh compound B (PiB) (Klunk, Engler et al. 2004) appears to
offer a promising advance towards better characterization of, and treatment for, such
underlying amyloid pathology. Such a development was hoped to have help close the
cognition-pathology gap. Unfortunately this gap remains very large in spite of this
important development.
Roe et al (Roe, Mintun et al. 2008) examined PiB amyloid load in relation to
measures of cognitive deterioration in a sample of elderly individuals with and
without diagnosed AD and did indeed find that those who were PiB positive showed
very significantly lower cognitive function and significantly higher clinical dementia
ratings than those who were PiB negative. There was one important caveat to this
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finding, however – this reassuring relationship between pathology and cognition
disappeared in the group with the highest levels (post-college) of education and was
significantly attenuated on most measures for those with intermediate education
(some college or graduate college education). The cognition-pathology gap among the
best educated in other words, widened to the extent that no correlation remained
between these two sets of variables.
Such findings do not just apply to education as a variable, however. In a study of
social networks (Bennett, Schneider et al. 2006), the researchers found that while
post-mortem pathology and pre-death cognition showed a reasonable correlation
among individuals with relatively sparse social networks, the cognition-pathology
correlation again disappeared – as in the case for education and cognition in Roe’s
PiB study – among groups with a high level of social contact and strong social
networks.
Discrepancies between cognition and pathology such as these have been explained by
the concept of ‘cognitive reserve’, a concept first developed by Yakov Stern (Stern,
Albert et al. 1999). Individual differences in the efficiency, capacity or flexibility of
brain networks (‘neural reserve’ in Stern’s terminology) or individual differences in
the ability to compensate for brain pathology (Stern’s ‘neural compensation’), may
allow brains affected by Alzheimer’s pathology to maintain adequate cognitive
functioning (Stern 2009).
The aim of this paper is not to review comprehensively the variables and processes
linked to cognitive reserve, as this has been well done elsewhere (Stern, Alexander et
al. 1992; Stern, Gurland et al. 1994; Stern, Albert et al. 1999; Valenzuela and Sachdev
2006; Tucker and Stern 2011). Nor does the paper attempt to elucidate the distinction
between cognitive reserve and the concept of ‘brain reserve’, which Stern and his
colleagues propose refers to intra-individual differences in biological substrates of the
brain leading to different degrees of resilience to the effects of disease or injury.
Cognitive reserve and brain reserve have been used interchangeably by other authors
such as Valenzuela and Sachdev (Valenzuela and Sachdev 2006), but the question
posed in this paper pertains to a hypothetical biological mediating mechanism by
which
either cognitive or brain reserve may shape the considerable pathology-
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cognition discrepancy commonly observed in Alzheimer’s Disease and other brain
disorders.
The magnitude of this cognition-pathology discrepancy is considerable, estimated by
Valenzuela and Sachdev in their meta-analysis of education, occupation, IQ and
mental activities components of brain reserve as a mean odds ratio of 0.54 for lowered
risk of incident dementia over a median 7.1 year period (Valenzuela and Sachdev
2006). There are three main theoretical interpretations of this finding.
The first is that the reserve variables and the reduced risk of AD diagnosis are
correlated not due to any direct causal link, but rather because each is associated with
a third common, possibly genetic, factor that causes both the high brain/cognitive
reserve factor (educational and occupational attainment and IQ) and the increased
resilience to the disease process. This view would hold that the observed correlation
between, say, education and lowered risk of AD, is therefore more reflective of the
pre-existing resilience than a direct effect of, say, education per se (Whalley, Deary et
al. 2004). A Swedish study of identical twins, however, showed that those who had
the minimal legal level of education for their age cohort had significantly higher
levels of dementia than their identical twins who had higher levels of education,
confirming that pre-existing genetic variables could not account for the cognitive
reserve-symptom relationship (Gatz, Mortimer et al. 2007).
The second theoretical explanation for this relationship is that the apparently
protective variables such as education build the brain’s capacity to compensate for a
disease process which in itself is unaffected by education, mental stimulation or social
interaction. Such compensatory variables could range from the increased cortical
volume that has been shown to arise from intensive new learning during exam
preparation in students (Draganski, Gaser et al. 2006) or by learning a new skill such
as juggling (Draganski, Gaser et al. 2004); it could also arise from cognitive-trainingrelated increases in white matter volume (Takeuchi, Sekiguchi et al. 2010) or from
changes to critical neurotransmitter receptor densities (McNab, Varrone et al. 2009).
Changes to brain regions crucial for compensatory adjustments such as the prefrontal
cortex may play a particular role (Erickson, Colcombe et al. 2007).
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The third theoretical explanation is that education, mental stimulation and social
interaction directly impact the Alzheimer’s Disease process itself, and not only the
brain’s capacity to compensate for the disease(Landau, Marks et al. 2012).
Only the second and third of these theoretical positions propose a causal role for the
protective effects of these cognitive reserve variables and the aim of this paper is to
advance a hypothesis about a possible biological route (enhanced noradrenergic
signaling) which might mediate between cognitive reserve and reduced AD
vulnerability in both of these theoretical cases 2 and 3 above, which I will term
‘compensatory’ and ‘disease modifying’ respectively. I ask in other words whether
variables such as education/IQ, mental stimulation and social engagement reduce risk
of AD by improving the brain’s ability to compensate for disease as outlined above
and/or by directly influencing the AD disease process itself. Because it is currently
not possible to measure directly brain noradrenergic function in vivo in humans,
however, it is first necessary to look to the animal literature on the cognitionpathology gap.
2. Environmental Enrichment and Neurodegeneration
Environmental enrichment improves cognitive function in a range of species. Dogs
randomly allocated to enriched environments over a period of more than two years in
one study showed lower amyloid plaque burden in their brains at post mortem than
dogs kept in standard environments (Pop, Head et al. 2010). Transgenic TgCRND8
Aβ-overproducing mice were randomly allocated to 60 days of enriched environment
before Aβ plaques appeared or 60 days after they had begun to appear (Herring,
Lewejohann et al. 2011), thus allowing comparison of the ‘preventative’ effects of
enrichment and the ‘therapeutic, post-disease-onset’ effects. They found that the
enriched environment before disease onset reduced the number and size of amyloid
plaques, which the authors suggest may occur due to increased degradation and
clearance of Aβ. ‘Therapy’, on the other hand, reduced the growth and fusion of
plaque seeds, possibly by inhibiting Aβ aggregation, the authors suggested.
These and several other studies (Lazarov, Robinson et al. 2005; Costa, Cracchiolo et
al. 2007) suggests that one aspect of cognitive reserve - enrichment/mental
stimulation - may at times directly influence various AD-linked pathologies, through
for instance NA amelioration of amyloid cellular toxicity, and not only influence the
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brain’s capacity to adapt to existing pathology. This series of studies suggest that
independently of any cognitive reserve-enhancing mechanisms that may be taking
place, allowing better adaptation to pathology, there are also effects of enrichment on
the pathologies themselves, thus perhaps increasing ‘neural reserve’, in Stern’s terms.
Recently, human evidence in favour of this hypothesis was obtained by Landau and
colleagues (Landau, Marks et al. 2012) who found a significant correlation between
estimated lifetime cognitive activity and amyloid burden the brain measured by PET
[11C]PiB β-Amyloid imaging in 65 people with a mean age of 76. Greater
participation in cognitively stimulating activities such as reading books or
newspapers, writing letters or e-mails, going to the library or playing games across the
lifespan was associated with reduced [11C]PiB while controlling for age, sex, and
years of education. Older participants in the highest cognitive activity group had
[11C]PiB uptake comparable to young controls, whereas those with lowest levels had
[11C]PiB uptake comparable to patients with AD. While greater cognitive activity was
associated with greater physical exercise, exercise however was not associated with
[11C]PiB uptake.
These two studies are in accord with the third theoretical position, namely that one
aspect of cognitive reserve - stimulation/enrichment - may directly impact the disease
process. Other studies, however, have found results more consistent with the second
theory, namely that of
compensatory capacity.
For instance, one study with
transgenic (APP) Aβ-overproducing mice, found that an enriched environment
normalized memory performance in these mice in spite of increased neuritic plaque
burden, a finding more consistent with the neural compensation hypothesis of
heightened resilience to extant pathology (Jankowsky, Melnikova et al. 2005) and a
similar finding was obtained with APPsw transgenic mice (Arendash, Garcia et al.
2004) and with APP-23 mice (Wolf, Kronenberg et al. 2006).
A similar conclusion has been reached in a longitudinal study of educational level in
humans, with 872 brain donors, of whom 56% were demented at death: these authors
found that while longer years in education were associated with decreased dementia
risk, this association was found to be statistically independent from the effects of
underlying pathology; this led them to conclude that the education mitigated the
impact of pathology rather than directly influencing pathological processes (Brayne,
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Ince et al. 2010). A similar conclusion was reached by another human study using
estimated premorbid IQ (American National Adult Reading Test) as a proxy marker
of lifetime environmental enrichment; the authors found that this measure of cognitive
reserve predicted cognitive performance independently of, and additively to, the
effects of amyloid and other measured pathologies (Vemuri, Weigand et al. 2011).
While environmental enrichment may build reserve both altering key pathologies
linked to Alzheimer’s Disease, the human evidence for this is weaker than the animal
data, and the strongest evidence is for such enrichment to help maintain improved
cognition through other, possibly compensatory, mechanisms. So how does
environmental enrichment produce its effects on cognition?
3. Mechanisms of Action of Environmental Enrichment on Cognitive Function
Environmental enrichment across a range of species improves cognitive function and
there are a range of mechanisms mediating these effects including neurogenesis,
synaptogenesis and increased levels of Brain Derived Neurotrophic Factor (BDNF)
and related neurotrophins, among others (vanPraag, Kempermann et al. 2000).
Reduced intracerebral inhibition and epigenetic changes at the level of chromatin
structure have also been implicated (Baroncelli, Braschi et al. 2010).
In addition,
environmental enrichment has significant effects on neurotransmitter function, and in
particular and in particular on noradrenergic tone.
Noradrenaline concentrations in brains of mice spending 40 days in enriched versus
standard environments increased significantly in parieto-temporo-occipital cortex, the
cerebellum and the pons/medulla oblongata
(Naka, Shiga et al. 2002) with no
corresponding changes observed in serotonin or dopamine levels in these brain
regions. Selective enrichment-induced modulation of noradrenaline release in mouse
hippocampus via pre-synaptic NMDA receptors has also been observed (Grilli,
Zappettini et al. 2009). The specific aspects of environmental enrichment that
improved a key cognitive function - memory - in mice, was investigated in another
study (Veyrac, Sacquet et al. 2008). These researchers compared enrichment via
novelty versus enrichment via complexity, in the context of odour enrichment and its
effects on odour memory. Daily exposure to single novel odorants improved memory
while daily exposure to a complex bouquet of odours which remained stable over the
enrichment period, did not. Furthermore, the daily changing single odour novelty
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condition produced increased neurogenesis in the olfactory bulb, while the stable
complex odour environment did not.
This study showed novelty as a key feature of the cognitively enriching and
neuroplasticity-enhancing aspects of the enriched environment. These positive effects
of enrichment were however mediated by noradrenaline, the authors showed, because
they were blocked under labetalol, a mixed b with a1- adrenoceptor antagonist. The
short term enhancing effects of novelty on hippocampal-dependent memory had
already been demonstrated, as had the mediating role of noradrenaline (Kitchigina,
Vankov et al. 1997). Furthermore, age-related LTP deficits in rats have been shown to
be significantly reduced by novelty, and these effects may be mediated
noradrenergically (Sierra-Mercado, Dieguez et al. 2008). In humans, Tulving and
colleagues found that the probability of long-term storage of information varies
directly with the novelty of the information(Tulving, Markowitsch et al. 1996).
Noradrenaline activation then, may be one important mechanism by which
environmental enrichment improves cognitive function, and novelty may be a key
feature of environmental enrichment’s beneficial effects. These effects would affect
the brain’s ability to compensate for disease - for instance by neurogenesis-induced
raised cortical volume, increased connectivity or other effects on brain structure and
function that would allow better compensation for the AD disease process. They
would not, however speak to the possibility of a direct effect on the disease process
itself. Is there then any evidence of a more specific relationship of NA function to
Alzheimer’s Disease?
4. Noradrenaline and Alzheimer’s Pathology
The locus coeruleus (LC) is the major source of NA in the brain and projects
synaptically and extra-synaptically to the entire cerebral cortex, as well as thalamic
nuclei, limbic structures and the hippocampus; the basal ganglia regions is the only
major structure that does not receive input from the LC (Sara 2009). While AD
research has strongly focussed on deficits in the cholinergic system (Babic 1999;
Terry and Buccafusco 2003; Ikonomovic, Klunk et al. 2011), a number of studies
have shown significant cell loss in the LC in Alzheimer’s Disease (Tomlinson, Irving
et al. 1981; Dringenberg 2000; Matthews, Chen et al. 2002; Szot, S.S et al. 2006;
Insua, Suáreza et al. 2010). In addition, LC degeneration is seen in very early, pre-AD
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disorders such as Mild Cognitive Impairment (MCI) and the drop in NA levels in
such patients is tightly linked to the progression and extent of memory dysfunction
and cognitive impairment (Grudzien, Shaw et al. 2007). Furthermore epidemiological
research shows that the dopamine β-hydroxylase -1021C/T polymorphism, which
influences NA availability in the brain, is a significant risk factor for AD, with
genotypes indicating low NA availability having as much as a doubled risk of AD
(Combarros, Warden et al. 2010).
The LC therefore may suffer early degeneration in the AD disease process. Since NA
plays a role as an anti-inflammatory molecule, one impact of the resulting decrease in
NA-ergic neurons is likely to be on inflammatory processes. NA, for instance, downregulates transcription of inflammatory genes in astrocytes and microglia (Feinstein,
Heneka et al. 2002), and reduces amyloid neural toxicity via anti-inflammatory
mechanisms, both in vitro and in vivo in APP mouse models (Heneka, Nadrigny et al.
2010). NA also stimulates BDNF production (Mannari, Origlia et al. 2008) which in
turn reduces amyloid toxicity on hippocampal neurons (Counts and Mufson 2010) and
also promotes neurogenesis (Masuda, Nakagawa et al. 2012). Furthermore, NA in
vitro has been shown to rescue cholinergic (Traver, Salthun-Lassalle et al. 2005) and
dopaminergic neurons (Troadec, Marien et al. 2001) by reducing oxidative stress;
more generally, NA also stimulates both DA and glutamate release in the brain
(Grinberg, Rueb et al. 2011). This combination of mechanisms - anti-inflammatory,
BDNF-increasing, neurogenesis-inducing, amyloid toxicity-reducing, amyloiddepleting, dopamine and cholinergic cell-rescuing, dopamine and glutamatestimulating, constitutes a set of NA-induced neuroprotective mechanisms which may
offer a possible biological basis for the phenomenon of cognitive or brain reserve.
Such mechanisms offer the theoretical possibility of a direct noradrenergicallymediated effect on the disease process and not just on the compensatory process.
5. Noradrenaline’s role in cognitive function
There is one critical missing link in the hypothesis outlined above. While
noradrenaline may have a number of neuroprotective and compensation-enhancing
effects on the brain, and cognitive reserve variables such as mental activity and
education may be associated with lower levels of AD pathology, is there any evidence
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that these cognitive reserve variables have any effects on NA function? To address
this question, a brief review of the role of NA in cognitive processes is required.
The brain’s locus coeruleus (LC)–noradrenaline system is crucially involved in task
engagement and optimizing performance according to environmental contingencies
(Aston-Jones and Cohen 2005). High-frequency phasic LC activity is elicited by
salient or task-relevant stimuli, and the resultant release of NA to the cerebral cortex
enhances stimulus processing by selectively increasing neuronal gain within taskrelevant regions - in short, it increases signal to noise ratio for important signals
(Aston-Jones, Chiang et al. 1991; Aston-Jones, Rajkowski et al. 1994; Sara 2009).
The role of phasic LC activity in facilitating stimulus processing is supported by
animal studies that highlight the phasic LC response as an important antecedent to
appropriate behavioral responding in stimulus detection paradigms (Aston-Jones,
Rajkowski et al. 1994; Usher, Cohen et al. 1999).
Based primarily on such intracranial recordings from animals, the adaptive-gain
theory of LC-NE function (Aston-Jones and Cohen 2005) states that relative levels of
tonic and phasic LC activity relate to task performance in a manner that reflects the
classic Yerkes–Dodson arousal curve (Yerkes and Dodson 1908): Performance and
phasic LC responding are optimal at an intermediate level of tonic LC activity, but
shifts toward either end of the tonic activity continuum are associated with declining
performance and nonspecific or attenuated phasic responses. The importance of this
LC arousal function in humans has been highlighted by pharmacological and genetic
studies that corroborate the role of NA as a critical determinant of engagement and
task performance on tests of attention (Smith and Nutt 1996; Coull, Nobre et al. 2001;
Minzenberg, Watrous et al. 2008; Greene, Bellgrove et al. 2009; Murphy, Robertson
et al. 2011).
Assessing NA levels directly in the living human brain is not currently possible, but
recent research suggests that LC/NA activity may be indexed by the pupillary
response to motivationally salient or novel stimuli (Aston-Jones and Cohen 2005;
Einhauser, Stout et al. 2008; Gilzenrat, Nieuwenhuis et al. 2010; Gabay, Pertzov et al.
2011; Jepma and Nieuwenhuis 2011), including in primates (Bouret and Richmond
2009). For many decades, pupil dilation has been shown to co-vary with ongoing
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cognitive processes in the human brain (Beatty 1982; Loewenfeld 1993). This is quite
distinct from the cholinergically-mediated hypersensitivity in pupil dilation response
to a cholinergic antagonist, tropicamide, that has been demonstrated in people
suffering from Alzheimer’s Disease (Scinto, Daffner et al. 1994), and also in a
reduced dilation response to light (Fotiou, Fountoulakis et al. 2000). In contrast to
this, the NA-based pupil dilation is a response to a number of different cognitive
challenges which shows considerable variation within and between health individuals
of all ages.
Cognitive or mental effort increases pupil size, in proportion to the difficulty or
challenge, across the domains of memory (Kahneman and Beatty 1966; Peavler
1974), problem-solving (Hess and Polt 1964; Bornemann, Foth et al. 2010), auditory
perceptual processing (Kahneman and Beatty 1967), attention (Murphy, Robertson et
al. 2011; Laeng, Ørbo et al. 2012) and mathematical cognition (Kahneman 1973),
among others. Furthermore, stimulation of the LC with consequent up-regulation of
NA activity has been shown to improve cognitive, perceptual and memory
performance in monkeys and rodents (Berridge and Waterhouse 2003; Sara 2009;
Bornemann, Foth et al. 2010).
Bearing in mind the evidence that human NA activity may be indexed by pupillary
responses to cognitive challenge, let us now consider the evidence for pupillary
dilation responses - our proxy marker for NA activity - in relation to the four
cognitive reserve variables.
6. Cognitive Reserve and Noradrenergic Function
Is there any evidence that four of the most common elements of ‘cognitive reserve’ Education/IQ, Mental Activity, Social Interaction and Enriched/Novel Environments influence noradrenergic activity as indexed by pupillary measures? Let us consider
each in turn.
Education/IQ
Education levels are very strong predictors of reduced risk of diagnosis with
Alzheimer’s Disease (Stern, Gurland et al. 1994; Kidron, Black et al. 1997; Gatz,
Mortimer et al. 2007; Stern 2009; Brayne, Ince et al. 2010; Dumurgier, Paquet et al.
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2010; Roe, Mintun et al. 2010) as are premorbid IQ levels (Tucker and Stern 2011;
Vemuri, Weigand et al. 2011), with education levels and the IQ Quotient being highly
correlated (Ceci and Williams 1997).
Van Der Meer and colleagues (Van Der Meer, Beyer et al. 2010) showed that adults
with higher than average IQ (fluid intelligence) showed similar pupil dilation to those
shown by people of average IQ. When the analogies were made more difficult,
however, the high IQ participants showed much bigger pupil dilation to these
problems, which the authors interpret as the deployment of greater cognitive
resources in those of higher intelligence; this finding was replicated by Bornemann et
al (Bornemann, Foth et al. 2010). Given the evidence that pupil dilation indexes
noradrenergic activity (Gilzenrat, Nieuwenhuis et al. 2010; Murphy, Robertson et al.
2011; Laeng, Ørbo et al. 2012), one element of the putative ‘resource’ in question is
likely to be increased noradrenaline levels. Increased NA levels improve and ‘clean’
neural signals in the brain (Sara 2009) and contribute to the increased level of optimal
arousal which more challenging tasks demand, in line with the original observation by
Yerkes and Dodson (Yerkes and Dodson 1908) and in line with what is known about
the inverted-U function of neurotransmitters such as NA(Arnsten, Steere et al. 1996).
These limited data offer some support to the hypothesis that Education/IQ may
influence cognitive reserve in part via the enhanced noradrenergic activity in the
brain, with possible resulting consequent neuroprotective or compensation-enhancing
downstream effects as outlined earlier in this article.
Mental Activity
Mental activity is correlated with reduced risk of Alzheimer’s Disease (Wang, Karp et
al. 2002; Verghese, Lipton et al. 2003; Valenzuela and Sachdev 2006; Wolf,
Kronenberg et al. 2006; Valenzuela and Sachdev 2009; Valenzuela, Matthews et al.
2011; Landau, Marks et al. 2012), though there is no consensus as to whether this is
purely due to mental activity’s effects in improving brain robustness (eg neuron
density), as Valuenzuela and colleagues have argued (Valenzuela, Matthews et al.
2011), or whether in addition actual AD pathology (eg amyloid load) may also be
affected(Landau, Marks et al. 2012).
Mental activity and engagement, however, robustly and reliably increases pupil
dilation, with the size of the dilation proportional to the level of the mental challenge
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(Kahneman 1973). This has been shown across a range of cognitive challenges,
ranging from auditory pitch discrimination (Kahneman and Beatty 1967) to the Stroop
effect, where the difficult incongruent words elicit a much greater pupillary response
than the congruent or control words (Laeng, Ørbo et al. 2012) and to perception of
ambiguous figures, where pupil dilation occurs immediately before the alternative
percept comes into awareness (Einhauser, Stout et al. 2008). Similar findings apply in
the memory domain, where pupils have been shown to dilate to a greater extent when
participants correctly remember previously learned items, even when the words were
presented acoustically. The pupil dilation was also greater when items when memory
encoding was deep compared to shallow (Otero, Weekes et al. 2011).
Undoubtedly mental activity, in particular challenging and engaging mental activity,
stimulates pupil dilation and therefore may be triggering NA release in the brain. To
the extent that over a lifetime a person is - maybe many hundreds of times per day repeatedly stimulating the locus coeruleus (LC) to secrete noradrenaline, this could
offer a possible mechanism by which such activity could both build a brain better able
to resist the disease process through mechanisms such as NA- and BDNF- enhanced
neurogenesis or synaptogenesis, for instance, and/or actually offer neuroprotection to
neurons through its anti-inflammatory and other related mechanisms as outlined
earlier.
Novelty
While novelty and change have not been regarded as contributing to cognitive reserve
in the human literature, the evidence cited earlier in this article on the role of
environmental enrichment on protecting against AD-type symptoms in rodents
suggested that novelty may be the crucial element mediating between effects of
enrichment and its beneficial neural and cognitive effects (Veyrac, Sacquet et al.
2008). Given that factors such as rich leisure and occupational activities throughout
life have been linked to cognitive reserve, the possibility arises in the light of
Veyrac’s study, that novelty may be a potentially potent component of these effects.
But is there any evidence that in humans, novelty has any specific effects on the
noradrenergic system? It seems that there is: Steiner and colleagues examined
electroencephalographic, skin conductance and pupil dilation responses to auditory
stimuli. While all three types of response were apparent in response to target tones,
the researchers found that ‘the pupillary dilation response, however, demonstrated an
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unexpected sensitivity to stimulus novelty only’ (p 1648) (Steiner and Barry 2011).
Other studies have shown a specific pupillary sensitivity to surprise, which is closely
linked to novelty (Reisenzein, Bördgen et al. 2006). To the extent that the pupillary
response is a marker of NA activity, there is therefore evidence that novelty - a
possible key factor in mediating rodent environmental enrichment effects - does
indeed selectively upregulate NA activity in humans also.
Social Interaction
Social interaction may be a special case of mental activity, but given that human
beings are a fundamentally social species, evolved to live in groups, it warrants
separate attention, particularly in the light of evidence that social networks can, like
education/IQ and mental activity, strongly moderate the relationship between AD
pathology and cognitive function, to the extent that no correlation between postmortem pathology and cognitive function while alive was found in individuals with
strong social networks (Bennett, Schneider et al. 2006). This finding has been
replicated (Crooks, Lubben et al. 2008), though a further study suggested that it may
be the quality more than the quantity of social networks that protects against
AD(Amieva, Stoykova et al. 2010).
There is relatively little direct evidence about the effects of social stimuli on pupil
dilation/NA response, though Kuchinke and colleagues showed that the pupil
response to words spoken with either positive or negative prosody was much larger
than to words spoken in a neutral voice (Kuchinke, Schneider et al. 2011).
7. Working Memory and Cognitive Reserve
IQ is one of the key elements of cognitive reserve (Stern 2009; Vemuri, Weigand et
al. 2011), and a considerable amount of research has shown that the central cognitive
component of fluid intelligence is working memory capacity - the ability to hold and
manipulate a constantly changing stream of information (Engle, Tuholski et al. 1999).
In that context, it is very interesting to note the results of a follow up of 801 elderly
individuals over a period of 4.5 years (Wilson, Mendes de Leon et al. 2002). In line
with previous studies on mental activity, the authors found that baseline participation
in cognitively stimulating activities was protective against subsequent cognitive
decline, with those at the highest - 90th percentile - of baseline cognitive activity
being 47% less likely to develop AD than were those at the lowest - 10th percentile -
15
of baseline mental activity: there was no such link with level of physical activity.
Furthermore, high baseline cognitive activity predicted a lower rate of cognitive
decline, but level of mental activity was specifically predictive of rate of change in
only two categories of cognitive function - working memory capacity and perceptual
speed. Level of baseline mental activity did not significantly predict rate of change of
other types of memory or of visuospatial ability, for instance.
Working memory capacity, therefore, may be a possible mediator between two
aspects of cognitive reserve – IQ and mental activity – on the one hand, and reduced
risk of cognitive decline on the other. This finding is particularly interesting given the
evidence that working memory capacity has been shown to be improvable with
training (Jaeggi, Buschkuehl et al. 2008; Klingberg 2010), and indeed to result in
alterations of dopamine receptor densities in prefrontal cortex (McNab, Varrone et al.
2009) as well as in increases in white matter density (Takeuchi, Sekiguchi et al.
2010). While perceptual speed is also a potential candidate mediator, and is also, like
working memory, trainable (Green and Bavelier 2003; McGugin, Tanaka et al. 2011),
the evidence for its biological effects are so far weak. On the other hand, NA seems to
play a crucial role in age-related decrements in working memory capacity: Wang and
colleagues showed that in primates, a significant age-related decrement in working
memory manifested in reduced delay-phase neuronal firing in prefrontal cortex, was
normalized by up-regulating the noradrenergic system (Wang, Gamo et al. 2011).
8. Conclusions and Implications
The question posed in this paper concerns a possible mechanism that may mediate
between cognitive reserve on the one hand, and reduced risk of Alzheimer’s Disease
diagnosis on the other. It is hypothesized that the key elements of cognitive reserve educational level, IQ, mental and social engagement - all involve up-regulation of the
noradrenergic system which is otherwise depleted with age - and that such
optimization of noradrenergic activity may reduce the risk of AD. The mechanisms by
which AD activity may be protective are multifarious but fall into two broad
categories, roughly in line with the compensatory and disease-modifying theories
outlined in the introduction.
The compensatory theory proposes that cognitive reserve is associated with a number
of non-specific changes to the brain - cortical volume, white matter density, synaptic
16
density, neurotransmitter receptor densities among others - and that the cognitionpathology gap is explained by a bigger and better connected brain being able to
reorganize around the pathology caused by the AD disease process. Noradrenaline
plays a key role in the learning and stimulation that underpins these cognitive reserve
variables because of its unique neuromodulation and long-term-potentiationenhancing (Harley 1987) characteristics and central role in mediating the effects of
environmental enrichment on neurogenesis, synaptogensis, the stimulation of BDNF
and many other mechanisms.
An early review made this observation about the LC/NA system: ‘ (it) affects
synapses throughout the CNS, suppressing most, but permitting or even accentuating
activity in those that are transmitting novel or significant stimuli...this favours the
development of persistent facilitatory changes in all synapses that are currently in a
state of excitation.’ (Kety 1972)
Kety also predicted that NA would have a crucial
role in the cornerstone of learning and neuronal plasticity, a prediction subsequently
confirmed after the discover of long-term potentiation, LTP (Harley 1987). This
included evidence that NA increases caused by stimulation of the LC improved
memory retrieval in rats (Devauges and Sara 1991) .
Sara’s review of the LC/NA system (Sara 2009) concluded that its intra and extracellular dispersion throughout the brain exceeded that of most other neurotransmitters,
with the only major region not receiving input from the LC being the basal ganglia.
Noradrenaline
is centrally and specifically involved in mediating environmental
stimulation, attention and learning and therefore is a strong candidate for mediating
the compensatory aspect of cognitive reserve. The resulting synaptogenesis and
neurogenesis, among other mechanisms, leads to a brain structure better able to resist
pathological processes; the human research (Brayne, Ince et al. 2010; Valenzuela,
Matthews et al. 2011) tends to support this compensatory model of mediation,
whereby the cognitive reserve acts brain’s ability to withstand the pathology.
But what about the pathology itself, does NA have a role, as the disease-modifying
model proposes, in reducing the AD pathology itself? The evidence from human
research is scanty, and where it does exist, does not tend to support this hypothesis.
The animal research, on the other hand, offers the possibility that in addition to the
17
compensatory mechanism, NA optimization may also reduce pathology, or at least
diminish the neural toxicity-inducing effects of pathology (Heneka, Nadrigny et al.
2010), and there is some limited human evidence in support of this also (Landau,
Marks et al. 2012).
The figure schematically outlines the hypothesized role of NA in cognitive reserve,
outlining the two possible modes of action that NA may have in facilitating both
compensation to the disease processes, and also to modifying the disease processes
themselves.
Figure about here
While accepting that the balance of the human evidence is for an indirectly protective
effect of cognitive reserve on resistance to pathology rather than on the pathology
itself - the compensatory theory - a hypothetical role for noradrenaline in mediating
between cognitive reserve and reduced risk of AD offers a number of potentially
useful lines of research to test this hypothesis. Mental stimulation or cognitive
enrichment effects may for instance be potentiated by noradrenergic agonists, with the
sorts of enhanced rehabilitation effects that have been found, for instance, in stroke
rehabilitation (Crisostomo and Duncan 1988; Walker-Batson, Curtis et al. 2001). Use
of possible NA markers such as pupil dilation my further offer a method for more
precisely measuring how cognitive reserve variables affect the ability to compensate
for neurodegenerative pathologies. If this is successful, then it may be possible to
quantify and hence control for these variables which otherwise complicate the
evaluation of novel pharmaceutical agents whose symptomatic effects may be
otherwise masked in patients with high cognitive reserve. Furthermore, by identifying
such a possible biological correlate of cognitive reserve, it may be possible to more
easily identify people in the very early stages of Alzheimer’s Disease, with a view to
offering pharmacological treatment before too much neuronal death has occurred
because of amyloid toxicity or other mechanisms. Finally, the intriguing possibility supported largely by animal research - that NA may directly affect the AD disease
process, is one which demands further testing and exploration.
Acknowledgements
I would like to thank Atlantic Philanthropies for their generous support of my
research in this area, through their funding of the NIEL (Neuroenhancement for
18
Inequalities in Elder Lives) programme at Trinity College Institute of Neuroscience. I
would also like to thank my colleagues Redmond O’Connell, Joshua Balsters, Sabina
Brennan, Robert Coen, Marina Lynch and Carlo Miniussi for their careful comments
and help with this manuscript, and Sabina Brennan for preparing the figure.
Disclosures
There are no conflicts or interest or other disclosures to make.
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Figure Legend
Schematic role of hypothesized role of noradrenaline in mediating between
cognitive reserve and reduced risk of AD.
27