A noradrenergic theory of cognitive reserve: implications for Alzheimer's disease

doi:10.1016/j.neurobiolaging.2012.05.019

Neurobiology of Aging

Volume 34, Issue 1, January 2013, Pages 298-308

https://doi.org/10.1016/j.neurobiolaging.2012.05.019 Get rights and content

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 despite 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 noradrenaline's key role in mediating cognitive reserve—by disease compensation, disease modification, or a combination of both—a viable hypothesis.

Section snippets

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 1 hand—amyloid plaques, neurofibrillary tangles, positron-emission tomography (PET)-measured cerebral perfusion or volumetric magnetic resonance imaging for instance—and measured cognitive function and real life performance on the other (McKhann et al., 2011). In the famous “nun study” for instance (

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 2 years in one study showed lower amyloid plaque burden in their brains at postmortem than dogs kept in standard environments (Pop et al., 2010). Transgenic TgCRND8 amyloid-β (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 et al., 2011

Mechanisms of action of environmental enrichment on cognitive function

Environmental enrichment across a range of species improves cognitive function and there is 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 et al., 2000). Reduced intracerebral inhibition and epigenetic changes at the level of chromatin structure have also been implicated (Baroncelli et al., 2010). In addition, environmental enrichment has

Noradrenaline and Alzheimer's pathology

The locus coeruleus (LC) is the major source of NA in the brain and projects synaptically and extrasynaptically 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 focused on deficits in the cholinergic system (Babic, 1999, Ikonomovic et al., 2011, Terry and Buccafusco, 2003), a number of studies have shown

Noradrenaline's role in cognitive function

There is a 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 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

Cognitive reserve and noradrenergic function

Is there any evidence that 4 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.

Working memory and cognitive reserve

IQ is one of the key elements of cognitive reserve (Stern, 2009, Vemuri 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 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 et al., 2002). In line with previous

Conclusions and implications

The question posed in this report concerns a possible mechanism that may mediate between cognitive reserve on the 1 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 upregulation 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

Disclosure statement

There are no conflicts or interest or other disclosures to make.

Acknowledgements

The author thanks Atlantic Philanthropies for their generous support of the author's research in this area, through their funding of the NIEL (Neuroenhancement for Inequalities in Elder Lives) programme at Trinity College Institute of Neuroscience; and colleagues Redmond O'Connell, Joshua Balsters, Sabina Brennan, Robert Coen, Marina Lynch, and Carlo Miniussi for their careful comments and help with the manuscript, and Sabina Brennan for preparing the figure.

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Regular articleReviewA noradrenergic theory of cognitive reserve: implications for Alzheimer's disease

Abstract

Section snippets

The cognition-pathology gap in Alzheimer's disease

Environmental enrichment and neurodegeneration

Mechanisms of action of environmental enrichment on cognitive function

Noradrenaline and Alzheimer's pathology

Noradrenaline's role in cognitive function

Cognitive reserve and noradrenergic function

Working memory and cognitive reserve

Conclusions and implications

Disclosure statement

Acknowledgements

Prog. Brain Res

Lancet Neurol

Brain Res. Brain Res. Rev

Neurobiol. Aging

Behav. Brain Res

Behav. Brain Res

Lancet Neurol

Neurobiol. Dis

Neurochem. Int

Int. J. Psychophysiol

Behaviour

Neuropsychologia

Neurobiol. Aging

Progr. Neuropharmacol. Biol. Psychiatry

Neurobiol. Dis.

Neurobiol. Aging

Trends Cogn. Sci

Neuropsychologia

Cell

Prog. Neuropsychopharmacol. Biol. Psychiatry

Biol. Psychiatry

Alzheimers Dement

Brain Res

Neuropsychologia

J. Neurol. Sci

Am. J. Geriatr. Psychiatry

Biol. Psychiatry

What aspects of social network are protective for dementia?Not the quantity but the quality of social interactions is protective up to 15 years later

Psychosom. Med

Environmental enrichment improves cognition in aged Alzheimer's transgenic mice despite stable beta-amyloid deposition

Neuroreport

The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive functionPotential significance for attention-deficit hyperactivity disorder

Arch. Gen. Psychiatry

An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance

Annu. Rev. Neurosci

Locus coeruleus neurons in monkey are selectively activated by attended cues in a vigilance task

J. Neurosci

The cholinergic hypothesis of Alzheimer's disease: a review of progress

J. Neurol. Neurosurg. Psychiatry

Nurturing brain plasticity: impact of environmental enrichment

Cell Death Differ

Task-evoked pupillary responses, processing load, and the structure of processing resources

Psychol. Bull

Mathematical cognition: individual differences in resource allocation

ZDM

Relation of locus coeruleus neurons in monkeys to pavlovian and operant behaviors

J. Neurophysiol

Schooling, intelligence, and income

Am. Psychol

The dopamine β-hydroxylase −1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project

BMC Med. Genet

The noradrenergic alpha2 agonist clonidine modulates behavioural and neuroanatomical correlates of human attentional orienting and alerting

Cereb. Cortex

Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity

J. Neurochem

Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients

Ann. Neurol

Social Network, Cognitive Function, and Dementia Incidence Among Elderly Women

Am. J. Public Health

Neuroplasticity: Changes in grey matter induced by training

Nature

Temporal and Spatial Dynamics of Brain Structure Changes during Extensive Learning

J. Neurosci

Education, the brain and dementia: neuroprotection or compensation?

Brain

Pupil dilation reflects perceptual selection and predicts subsequent stability in perceptual rivalry

Proc. Natl. Acad. Sci. USA

Regular article
Review
A noradrenergic theory of cognitive reserve: implications for Alzheimer's disease