Characterising brain network differences during scene perception and memory in young adult APOE-e4 carriers: multi-modal imaging in ALSPAC

Approximately 850,000 people in the UK have dementia; by 2025, this will increase to over one million, and by 2050 is projected to exceed 2 million. The annual financial cost of neurodegenerative disease to the UK economy is over £24 billion and rising; yet delaying dementia onset by just 5 years could reduce these costs by half. The earlier that potential interventions can be implemented, therefore, the greater the benefit for improving health and the greater the opportunity to reduce the economic and societal burden of dementia.

Key to knowing when and in whom to apply preventative interventions is the identification of at-risk individuals prior to the onset of age-related cognitive decline. Here, we view 'vulnerability' to poorer cognitive health in later life as not exclusively related to 'aging', but instead, to the accumulation of risks across the lifespan. This account predicts that some of the cognitive and brain differences evident in later life can be predicted by early life factors, and lends itself to the study of young healthy individuals who are at heightened risk of age-related cognitive decline via possession of genes associated with cognitive disorders of ageing.

In this research proposal, we focus on the potential influence of one such common semi-dominant risk allele, APOE-e4, by asking: (a) whether healthy APOE-e4 carriers in early adulthood show selective brain and behavioural differences (compared to non-carriers) that are consistent with the early cognitive and anatomical markers of detrimental aging, and (b) how such early life effects may be moderated by cognitive reserve, gender and lifestyle factors.

A large-scale neuroimaging study will be undertaken in young adults from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort, including novel application of 7T MRI which allows detailed assessment of key brain structures in the medial temporal lobe (e.g., hippocampus). This approach, which is founded on strong pilot evidence for early life brain network changes in young APOE e4 carriers (particularly during scene perception and memory) will identify the circumstances under which such cognitive changes in young at-risk individuals are seen, ask whether these brain network alterations are linked to behavioural performance (e.g., successful perception and memory), and determine how this early life cognitive vulnerability may be moderated by gender, lifestyle and cognitive reserve.

Key to reducing the burden of poorer cognitive health in later life (e.g., by delaying disease onset) is the identification of high-risk individuals prior to the onset of cognitive decline. Here, we test the hypothesis that 'vulnerability' to poorer cognitive health in later life may not be exclusively related to 'aging', but instead, to the accumulation of risks across the lifespan. We will investigate whether young healthy individuals, who are at heightened risk of age-related cognitive decline via possession of an allele (APOE-e4) associated with cognitive disorders of ageing (including Alzheimer's disease), show brain and behavioural differences, compared to non-carriers, that are consistent with the early anatomical and cognitive markers of ageing. A multimodal cognitive imaging approach will be applied involving functional and structural imaging at both 3T and 7T (the latter enabling high-resolution segmentation of subfields in the medial temporal lobe). By applying this in individuals from the Avon Longitudinal Study of Parents and Children, who have been studied from birth, and are now aged 26yrs, we will additionally be able to ask how such early life effects may be moderated by cognitive reserve (e.g., childhood IQ), gender and lifestyle factors (e.g., diet, smoking, alcohol and/or exercise).

This study will be used to test the overall hypothesis that: APOE-e4 may influence the onset of cognitive decline in later life via its impact on functional and structural connectivity in a brain circuit involving posteromedial cortex and the medial temporal lobe. More specifically, we predict that young healthy APOE-e4 carriers will show specific brain and behavioural differences (compared to non-carriers) linked to scene perception and memory, and that these effects will be moderated by cognitive reserve, gender and lifestyle factors.

Who will benefit from this research?

This project has been designed to have an impact beyond the academic sector, in particular by testing the hypothesis that there may be early life markers of later life risk of age-related cognitive decline. Key outcomes include new understanding of early life functional and structural brain differences in carriers of the APOE-e4 allele (compared to individuals carrying the risk neutral APOE-e3 allele), and how these brain activity patterns in APOE-e4 individuals might be predictive of behaviour, as well as moderated by factors, such as health behaviours and cognitive reserve. In the longer-term, this work is likely to lead to novel cognitive assessment tools able to be applied across the lifespan, and used to identify individuals at heightened risk of age-related cognitive decline. Such an approach is vital for decision-making relevant to the timing and appropriateness of interventional approaches.

Three major beneficiaries have been identified: (1) Health professionals involved in the early detection of age-related cognitive decline. (2) Providers of cognitive assessment software, imaging manufacturers and pharmaceutical companies interested in novel neuro- and cognitive-therapeutics. (3) Charitable organisations involved in dementia health policy.

How will they benefit from this research?

These groups will benefit from new knowledge that informs our understanding of the very earliest brain changes in APOE-e4 carriers, specifically which cognitive domain is most sensitive to APOE-e4 status in young individuals and how such differences relate to behaviour. Our imaging will facilitate optimisation of (a) the sensitivity of different functional and structural imaging approaches (separately or together) to APOE-e4 status and (b) help develop new MR-based imaging methods and analysis tools, especially relevant to ultra-high field MRI. These new approaches can be readily implemented in other MR centres via the cross-University team associated with this project, and CUBRIC's strong connectivity with other UK and European centres. Finally, this research will establish a unique multimodal imaging data set for further longitudinal studies relevant to a number of diseases.

What will be done to ensure that they benefit from this research?

To ensure the broadest dissemination of our findings, we will participate in relevant meetings and workshops, most often with leading individuals in the health, charitable, software and pharmaceutical sectors. Our involvement in UK-wide research networks are particularly valuable in this context, providing unique opportunities for bidirectional engagement with other UK and European researchers, as well as leaders in the pharmaceutical industry and software developers. For example, Mackay is Informatics Lead for the Dementias Platform UK, with the remit to develop accessible imaging data and new informatics approaches. The new CUBRIC has a partnership with Siemens which enables bidirectional knowledge transfer relevant to augmenting imaging acquisition and analysis approaches, particularly for ultra-high field MR. Working with scientists and engineers at Oxford, Graham is contributing to the development of new wearable technology for tracking of cognitive function. The basic science proposed here is vital for the success of these impact outcomes, aimed at revolutionising the way in which we assess cognition across the lifespan, including generation of statistical and informatics approaches that enable assessment of potential interventional approaches designed to reduce the impact of age-related cognitive decline.