The APOE paradox: how do attentional control differences in mid-adulthood reflect risk of late-life cognitive decline

Possession of an APOE e4 allele is an established risk factor for Alzheimer’s disease, while the less commonly studied e2 variant is premised to offer some protection. This research explores the purported deleterious-protective dichotomy of APOE variants on attentional control in mid-adulthood. 66 volunteers, aged 45-55 years, completed three tasks that provided complementary measures of attentional control: prospective memory, sustained attention and inhibition. Performance was compared between e2 carriers, e4 carriers and e3 homozygotes (the population norm). Carriers of the e4 allele showed subtle disadvantages, compared to the e3 group, in accuracy of Stroop task and prospective memory performance. Contrary to expectations, e2 carriers showed performance disadvantages in sustained attention. The finding of detrimental effects in attentional control for both e4 and e2 complicates the current model that proposes opposing effects of these variants on later-life cognition. Future research is needed to understand how cognitive differences develop with increasing age, and the physiological mechanisms that underpin these changes

Apolipoprotein ε4 and attentional control: understanding the trajectory of cognitive ageing from mid-life

The greatest genetic factor in how well we age cognitively is Apolipoprotein E (APOE), a single nucleotide polymorphism with three allelic variants: epsilon-2, epsilon-3 and epsilon-4 (hereafter ε2, ε3, ε4). The ε4 allele is associated with an increased risk of cognitive disadvantage in later life, however, the effects of this variant are not isolated to old-age, with some studies reporting cognitive advantages in youth. This thesis investigates the influence of APOE ε4 on cognition from mid-adulthood, a point in the lifespan when the detrimental effects of this allele may be emerging. This thesis begins with a systematic review and meta-analysis of the literature to-date, and suggests attention may be sensitive to ε4 differences in mid-adulthood, however, effects of the allele are not consistently shown, perhaps due to methodological limitations including the use of insensitive neuropsychological batteries (Chapter 1). Next, behavioural paradigms providing a sensitive index of both selective (Chapter 2) and executive attention (Chapter 3), suggest many attentional processes are intact in mid-age (45-55 years) ε4 carriers. Subtle deficits, however, are apparent on prospective memory (PM) and Stroop-switch paradigms, indicating a goal maintenance disadvantage. In addition, a proxy of cognitive reserve was found to moderate the effects of ε4 on executive attention in mid-adulthood (Chapter 4). Follow-up research used paradigms that target the distinct processes supporting focal and non-focal PM to interrogate the profile of change observed in mid-age ε4 carriers, identifying a profile of disadvantage consistent with that observed in pathological ageing (Chapter 5). PM, however, was not found to differentiate ε4 carriers in older individuals at heightened risk of converting to dementia (Chapter 6). Collectively, this research provides evidence for a profile of accelerated ageing in ε4 carriers, with subtle disadvantages apparent in executive attention by the end of the 5th decade

The elusive nature of APOE ε4 in mid-adulthood: understanding the cognitive profile

Objectives: The apolipoprotein E (APOE) ε4 allele is an established risk factor for dementia, yet this genetic variant is associated with a mixed cognitive profile across the lifespan. This study undertakes both a systematic and meta-analytic review of research investigating APOE-related differences in cognition in mid-adulthood, when detrimental effects of the allele may first be detectable. Methods: Thirty-six papers investigating the behavioral effects of APOE ε4 in mid-adulthood (defined as a mean sample age between 35 and 60 years) were reviewed. In addition, the effect of carrying an ε4 allele on individual cognitive domains was assessed in separate meta-analyses. Results: The average effect size of APOE ε4 status was non-significant across cognitive domains. Further consideration of genotype effects indicates preclinical effects of APOE ε4 may be observable in memory and executive functioning. Conclusions: The cognitive profile of APOE ε4 carriers at mid-age remains elusive. Although there is support for comparable performance by ε4 and non-e4 carriers in the 5th decade, studies administering sensitive cognitive paradigms indicate a more nuanced profile of cognitive differences. Methodological issues in this field preclude strong conclusions, which future research must address, as well as considering the influence of further vulnerability factors on genotype effects

Impairment in Theory of Mind in Parkinson’s Disease Is Explained by Deficits in Inhibition

Objective. Several studies have reported that people with Parkinson's disease (PD) perform poorly on tests of 'Theory of Mind' (ToM), suggesting impairment in the ability to understand and infer other people's thoughts and feelings. However, few studies have sought to separate the processes involved in social reasoning from those involved in managing the inhibitory demands on these tests. In this study, we investigated the contribution of inhibition to ToM performance in PD. Methods. 18 PD patients and 22 age-matched healthy controls performed a ToM test that separates the ability to infer someone else's perspective from the ability to inhibit one's own. Participants also completed a battery of standard measures of social and executive functioning, including measures of inhibition. Results. The PD patients performed worse on the ToM test only when the inhibitory demands were high. When the level of inhibition required was reduced, there were no significant group differences. Furthermore, executive impairments in PD patients were limited to measures of inhibition, with disadvantages associated with poorer ToM performance in this group. Conclusions. This study provides convincing evidence that the apparent impairment observed on ToM tests in PD is explained by deficits in inhibition

Pilot and feasibility studies : extending the conceptual framework

Acknowledgements Not applicable. Funding No specific funding was received for this work.Peer reviewedPublisher PD

Development and validation of a short form psychometric tool assessing the caregiving Challenge of Living with Cystic Fibrosis (CLCF-SF) in a child.

ObjectiveCaring for a child with cystic fibrosis (CF) is a rigorous daily commitment for caregivers and treatment burden is a major concern. We aimed to develop and validate a short form version of a 46-item tool assessing the Challenge of Living with Cystic Fibrosis (CLCF) for clinical or research use.DesignA novel genetic algorithm based on 'evolving' a subset of items from a pre-specified set of criteria, was applied to optimise the tool, using data from 135 families.Main outcome measuresInternal reliability and validity were assessed; the latter compared scores to validated tests of parental well-being, markers of treatment burden, and disease severity.ResultsThe 15-item CLCF-SF demonstrated very good internal consistency [Cronbach's alpha 0.82 (95%CI 0.78-0.87)]. Scores for convergent validity correlated with the Beck Depression Inventory (Rho = 0.48), State Trait Anxiety Inventory (STAI-State, Rho = 0.41; STAI-Trait, Rho = 0.43), Cystic Fibrosis Questionnaire-Revised, lung function (Rho = -0.37), caregiver treatment management (r = 0.48) and child treatment management (r = 0.45), and discriminated between unwell and well children with CF (Mean Difference 5.5, 95%CI 2.5-8.5, p p = 0.039).ConclusionThe CLCF-SF provides a robust 15-item tool for assessing the challenge of living with a child with CF

Putting attention in the spotlight: the influence of APOE genotype on visual search in mid adulthood

The Apolipoprotein E e4 allele is associated with greater cognitive decline with age, yet effects of this gene are also observed earlier in the lifespan. This research explores genotype differences (e2, e3, e4) in the allocation of visuospatial attention in mid-adulthood. Sixty-six volunteers, aged 45–55 years, completed two paradigms probing the active selection of information at the focus of attention (a dynamic scaling task) and perceptual capacity differences. Two methods of statistical comparison (parametric statistics, Bayesian inference) found no significant difference between e4 carriers and the homozygous e3 group on either the dynamic scaling or perceptual load task. E2 carriers, however, demonstrated less efficient visual search performance on the dynamic scaling task. The lack of an e4 difference in visuospatial attention, despite previous suggestion in the literature of genotype effects, indicates that select attentional processes are intact in e4 carriers in mid-adulthood. The association of e2 genotype with slower visual search performance complicates the premised protective effects of this allele in cognitive ageing

Transformative governance for ocean biodiversity

This Chapter analyzes the major underlying causes of marine biodiversity loss and focuses specifically on the lessons learnt for transformative ocean governance in the context of area-based management and spatial planning. It illustrates the broad recognition of the vital need for integrative, anticipatory, adaptive and inclusive governance of ocean biodiversity. Fundamentally, however, the Chapter underscores the need for transdisciplinary governance in supporting integration, inclusion and learning in ocean affairs for transformative change. An alternative governance approach is proposed: building on the inter-dependencies between human rights and marine biodiversity, a broader approach to fair and equitable benefit-sharing can support institutionalized shifts towards more transdisciplinary, integrative, inclusive and adaptive governance for the ocean at different scales

Transformative governance for ocean biodiversity

The ocean’s enormity and depth are illustrated by the limited ability of humankind to comprehend it. The current science and policy seascape remains largely fragmented, and as a result the integrity of marine life and the well-being of those (human and nonhuman) dependent on a healthy ocean is being negatively impacted. Fragmented governance is an indirect driver of ocean biodiversity loss due to its inability to provide synergistic solutions to address simultaneously multiple direct drivers for such loss (overfishing, land-based and marine pollution, and climate change). This governance problem is well known (Kelly et al., 2019; Watson-Wright and Valdés, 2018), and to some extent it is being addressed in ongoing international negotiations on an international instrument on marine biodiversity of areas beyond national jurisdiction (A/RES/72/249, 2017)

Development and validation of a short form psychometric tool assessing the caregiving Challenge of Living with Cystic Fibrosis (CLCF-SF) in a child.

Caring for a child with cystic fibrosis (CF) is a rigorous daily commitment for caregivers and treatment burden is a major concern. We aimed to develop and validate a short form version of a 46-item tool assessing the Challenge of Living with Cystic Fibrosis (CLCF) for clinical or research use. A novel genetic algorithm based on 'evolving' a subset of items from a pre-specified set of criteria, was applied to optimise the tool, using data from 135 families. Internal reliability and validity were assessed; the latter compared scores to validated tests of parental well-being, markers of treatment burden, and disease severity. The 15-item CLCF-SF demonstrated very good internal consistency [Cronbach's alpha 0.82 (95%CI 0.78-0.87)]. Scores for convergent validity correlated with the Beck Depression Inventory (Rho = 0.48), State Trait Anxiety Inventory (STAI-State, Rho = 0.41; STAI-Trait, Rho = 0.43), Cystic Fibrosis Questionnaire-Revised, lung function (Rho = -0.37), caregiver treatment management (  = 0.48) and child treatment management (  = 0.45), and discriminated between unwell and well children with CF (Mean Difference 5.5, 95%CI 2.5-8.5,  < 0.001), and recent or no hospital admission (MD 3.6, 95%CI 0.25-6.95,  = 0.039). The CLCF-SF provides a robust 15-item tool for assessing the challenge of living with a child with CF