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

Lead Research Organisation: Cardiff University
Department Name: Sch of Psychology

Abstract

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 evidece 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.

Technical Summary

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.

Planned Impact

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.

Publications

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Chandler HL (2020) Polygenic risk for Alzheimer's disease shapes hippocampal scene-selectivity. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Hodgetts CJ (2020) The role of the fornix in human navigational learning. in Cortex; a journal devoted to the study of the nervous system and behavior

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Karahan E (2019) Cognitive and White-Matter Compartment Models Reveal Selective Relations between Corticospinal Tract Microstructure and Simple Reaction Time. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Postans M (2020) Uncovering a Role for the Dorsal Hippocampal Commissure in Recognition Memory. in Cerebral cortex (New York, N.Y. : 1991)

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Williams AN (2019) On the sensitivity of event-related potentials to retrieval mode. in Brain and cognition

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Williams AN (2019) How the Human Brain Segments Continuous Experience. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description Wellcome Trust Institutional Strategic Support Fund
Amount £50,000 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom
Start 02/2018 
End 02/2019
 
Title Hippocampal Subfields Consortium 
Description Development of standardised approaches to assessment of hippocampal subfields via engagement in international hippocampal subfields consortium 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2018 
Provided To Others? No  
Impact Bringing together researchers to work collaboratively on protocols for imaging, and in time the development of a standardised tool for the community. 
URL http://www.hippocampalsubfields.com
 
Description Avon Longitudinal Study of Parents and Children (Bristol University) 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution Bringing new digital technological solutions to cognitive data collection in ALSPAC, enhancing cognitive phenotyping in mums and children.
Collaborator Contribution Facilitating data collection and analysis of large-scale cohort data, as well as access to retrospective data in participants able to answer new scientific questions regarding the genesis of cognitive inter-individual differences.
Impact Funding for a Wellcome Trust Institutional Strategic Support Fund award to obtain new cognitive data in mums within ALSPAC.
Start Year 2017
 
Description Global Brain Health Institute 
Organisation Trinity College Dublin
Country Ireland 
Sector Academic/University 
PI Contribution Two partners are leads of the major Global Brain Health Institute; engage with this via submission of potential applicants for their new dementia fellowship training programme but also via dissemination of new methods to address dementia. Working in partnership with Global Brain Health Institute has also
Collaborator Contribution Two partners are leads of the major Global Brain Health Institute; engage with this via submission of potential applicants for their new dementia fellowship training programme but also via dissemination of new methods to address dementia. Working in partnership with Global Brain Health Institute has also enabled new collaborations with low-to-middle income countries, aligned to funding for global challenges work.
Impact Joint grant funding - MR/P024696/1 - Developing low-cost cognitive tools for dementia assessment in low-to-middle income countries (LMICs)
Start Year 2017
 
Description Global Brain Health Institute 
Organisation University of California, San Francisco
Country United States 
Sector Academic/University 
PI Contribution Two partners are leads of the major Global Brain Health Institute; engage with this via submission of potential applicants for their new dementia fellowship training programme but also via dissemination of new methods to address dementia. Working in partnership with Global Brain Health Institute has also
Collaborator Contribution Two partners are leads of the major Global Brain Health Institute; engage with this via submission of potential applicants for their new dementia fellowship training programme but also via dissemination of new methods to address dementia. Working in partnership with Global Brain Health Institute has also enabled new collaborations with low-to-middle income countries, aligned to funding for global challenges work.
Impact Joint grant funding - MR/P024696/1 - Developing low-cost cognitive tools for dementia assessment in low-to-middle income countries (LMICs)
Start Year 2017
 
Description Article for Conversation 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Article on Alzheimer's disease and early changes to the brain, including coverage of the awarded grant
Year(s) Of Engagement Activity 2019
URL https://theconversation.com/alzheimers-carriers-of-risk-gene-show-brain-changes-in-their-20s-heres-w...
 
Description Cardiff Brain Games & Primary Assemblies 2015 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact All day public engagement activity aimed at KS2 school-children and their parents, held in the Cardiff Museum. It involves presentations, workshops and demonstrations.
Year(s) Of Engagement Activity 2014,2015,2016,2017
URL http://sites.cardiff.ac.uk/cubric/3200-visitors-to-the-cardiff-university-brain-games/
 
Description Cardiff Sciscreen - Away From Her 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Gave a talk / took part in a debate regarding the film Away From Her, related to forms of dementia
Year(s) Of Engagement Activity 2016
 
Description Newspaper article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Wrote an article on different forms of dementia for major national Welsh newspaper.
Year(s) Of Engagement Activity 2017
 
Description Pint of Science, Beautiful Mind 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Took part in presentation and debate around memory and dementia for Pint of Science. Almost 100 members of the general public attended the event, and increased interest in Cardiff University research and participation in research was achieved.
Year(s) Of Engagement Activity 2017