Rising to the Challenge: Understanding causes and consequences of neural overactivation in young adult APOE-e4 carriers

Apolipoproteins (APOs) form a diverse family of proteins with important functions in all cells. There are two major subtypes and several classes and sub-classes, one of which is APOE This protein is expressed in the brain, where it has a role in neurogenesis, plasticity and repair. APO-E has attracted most attention because one of its three forms (APOE-e4) is the single most important known genetic risk factor for late onset Alzheimer's disease. Also, healthy older carriers of the e4 variant suffer a steeper decline in intellectual ability in older adulthood than do non-carriers.
Intriguingly, recent experiments in my laboratory and others establish the surprising finding in young adult e4 carriers that they can out perform non-carriers on tasks requiring mental concentration. Brain scans performed on these young adults revealed that their brains differed from non-carriers in showing increased levels of activation in key brain regions when completing cognitive tasks. Comparing e4 carriers at young (18-28 years) and mid (45-55 years) adulthood, we found that brain activity in mid-adult e4 carriers resembled that normally seen in healthy older (70+) volunteers. This provides us with an experimental hypothesis for the paradoxical effects observed in e4 carriers across the lifespan. In sum, we suggest that e4 carriers are manifesting unusual brain activations from early adulthood, and that this produces two consequences. 1. It places undue metabolic stress on regions of the brain important for mental activity, 2. It exhausts the capacity for later-life compensatory activations in task-relevant regions and necessitates age-inappropriate recruitment of other brain regions in order to respond to task demands.
Building on the last BBSRC project, we propose to look at behaviour and brain activation patterns in young e4 carriers exposed to a particular set of psychological challenges. The aim of this proposal is to determine when, and why, young adult e4 carriers' brains overactivate in response to cognitive challenge. We will find out if the overactivity is limited to particular modes of cognitive processing, whether it is always present or reactive to task demands, and, importantly, whether it is plastic enough to enable it to be 'switched off' under certain circumstances. In addition, we will test the relationship between brain overactivity and the release of damaging brain substances associated with challenge and stress, thereby linking the brain activity directly to a potential mechanism through which the e4 variant of APOE exerts negative long term brain changes.
Research outcomes will be: 1) an improved understanding of the early life consequences of carrying the e4 variant of APOE 2) the identification of cognitive operations that elicit brain overactivations in e4 carriers, and 3) an understanding of the mechanisms that link overactivity to release of damaging stress-hormones in the young adult brain. Together these advances will directly inform the development of behavioural and cognitive strategies and techniques which can be recommended to carriers of e4. This we propose would mitigate the effects of brain overactivation and thereby enhance the prospects for healthy cognitive ageing in older adulthood. As such, this work relates directly to the current priority "Ageing research: lifelong health and wellbeing" and to Strategic priority 3 in the Strategic plan, to "Generate new knowledge of the biological mechanisms of ageing" and deliver "fundamental bioscience for better health and improved quality of life across the lifecourse, reducing the need for medical and social intervention".

The e4 variant of apolipoprotein E (APOE-e4) has attracted attention as the single most important known genetic risk factor for late onset Alzheimer's disease. It is also associated with steeper age-related decline in cognitively intact older adults. Paradoxically, experiments in my laboratory and others have established that young adult carriers of APOE e4 significantly out perform non-carriers on tasks placing demands on sustained attention, achieving this through a distinct pattern of overrecruitment of brain regions in response to cognitive challenge. We suggest that this early life overactivation has two consequences: 1. it places unusual metabolic stress on key brain regions, 2. it exhausts the capacity for compensatory activations normally recruited as part of healthy aging. Building on this work, and using a unique combination of behavioural, brain imaging, neuropharmacology and pupilometry techniques, this proposal will establish whether e4 overactivation is limited to particular modes of processing, whether it is related to the amount of effort engaged by the task, and whether the overactivity can be 'switched off' under defined conditions. In addition, we will test the relationship between brain overactivity and the release of cortisol, thereby linking the brain activity directly to a potential mechanism through which long-term brain changes occur. Research outcomes will be: 1) an improved understanding of the early life consequences of carrying the e4 variant of APOE, 2) the identification of factors that modulate brain overactivations of in e4 carriers, and 3) an understanding of the mechanisms that link chronic overactivity to metabolic stress, as indexed by cortisol release. Together these advances will directly inform the development of behavioural and cognitive strategies and techniques which can be recommended to young carriers of e4 in order to mitigate the effects of brain overactivation and enhance the prospects for healthy cognitive ageing.

This proposal will add significantly to the BBSRC's portfolio of research in the key priority area of Ageing Research: Lifelong health and wellbeing. The cognitive difficulties that arise with aging pose a challenge for care systems and societies worldwide. However, levels of age-related cognitive decline vary considerably between individuals, suggesting that such declines can be ameliorated by a thorough understanding of the genetic factors that affect cognition across the lifespan. The ApoE gene has a proven link to age-related cognitive decline, and our current BBSRC funded work has identified specific neural mechanisms which could underlie these declines. The experiments outlined here will extend the current work and assess the significance and potential modifiability of these mechanisms, which could lead to the development of cognitive or pharmaceutical interventions to normalise neural activity in at-risk individuals. In the long term it will therefore enhance quality of life, health and well-being.

The research findings themselves will be beneficial to individuals and organisations in academic, public, private and voluntary sectors. The outcome of these studies will be of interest to academic and clinical audiences in psychology and psychiatry. The findings will have significant implications for models of cognitive resilience in relation to aging, in particular, how genotypic influences on cognitive aging might be driven by effects present in young adulthood.

From a societal perspective understanding factors that mediate cognitive abilities across the lifespan could influence life choice decisions that impact on health and wellbeing. This work has direct relevance to the development of strategies to strengthen resilience to age-related decline across the lifespan, promoting successful cognitive ageing and greater quality of later life. It should therefore be of interest to local and national government and agencies concerned to promote wellbeing and to encourage new ways to remediate changes in cognitive abilities that naturally emerge over the lifespan.

As well as building capacity through engaging young researchers, Simon Evans (the Postdoctoral Researcher Co-investigator), will benefit from training in new techniques including pupillometry and neuropharmacology, as well as access to training in both research-specific and generic skills at Sussex. He would remain a member of the University of Sussex Doctoral School, which supports postdocs across the University, and a member of the thriving Biological and Clinical Neuroscience research group in the School of Psychology.

The University Press and Communications Office supports the communication of findings to the general public, providing support both in writing of press releases and advice on talking to journalists. They publish research findings in the Internal University Bulletin and send press releases to the media. These releases will encourage broader engagement with the work beyond the anticipated publications in peer-reviewed scientific journals, and international and national conferences.