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

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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".