Finding suitable and easily measurable early biomarkers for neurodegeneration and cognitive dysfunction represents the next frontier for prevention and early intervention strategies in diseases like Alzheimer’s Disease (AD). Our collective work in preclinical models has demonstrated that early-life adversity, such as stress or poor nutrition, can increase AD vulnerability, aggravate neuropathology and accelerate cognitive dysfunction. Neuroinflammation (driven by the brain’s primary immune cells, microglia) has been increasingly acknowledged as an important player in AD pathology and early-life adversity primes microglia, rendering them more sensitive to subsequent challenges. In addition, polyunsaturated fatty acids (PUFAs) and their derivatives play a key role in modulating microglia. N-3 PUFA (omega-3) metabolism is altered by early-life adversity and, recently, specialized pro-resolving mediators (SPMs; derivatives of omega-3) have been found to be altered in post-mortem AD brains. Finally, inflammation and metabolism are tightly connected in the context of early-life adversity and AD, presenting an opportunity to use metabolic sensors as potential biomarkers of (neuro)inflammation. We thus propose a translational project that will leverage data and bio-samples from four established human cohorts as well as more than 10 established in vivo and in vitro mouse and rat preclinical models. We will use these to identify early biomarkers of neurodegeneration and establish the causal role of and detailed mechanisms for early-life adversity and omega-3 in microglial priming in increasing the risk of neurodegeneration and AD. SOLID will complete a discovery program in humans aimed at identifying early biomarkers of neurodegeneration and cognitive decline. The second, parallel, work program will be to back-translate candidate and newly identified biomarkers to validated animal models of cognitive decline and AD and test the temporal and causal relationship of these biomarkers to the central neuroinflammatory changes. We will use several innovative approaches including microglial functional assays, microglia depletion strategies, omega-3 and SPM assessment, organotypic slice cultures, and transgenic rodent models; testing the causal role of early-life adversity, omega-3 and microglia. The third work program will test the potential for early supplementation with omega-3 to protect against early-life adversity-induced aggravation of neurodegeneration in AD mice and against cognitive deficits in a healthy aging human population. On completion of this proposal, we will have identified i) unique profiles of early biomarkers (cytokines, PUFAs, SPMs and metabolic sensors) predictive of cognitive dysfunction and neurodegeneration; ii) the causal role of early-life adversity in predisposition to AD; and iii) an omega-3 and SPM strategy for alleviating these effects.

Modern slavery is a pervasive and persistent problem with estimates that globally 24.9m people are in forced labour. Eradicating modern slavery is a grand challenge made arduous by ongoing COVID-19 effects that are increasing commercial priorities in business decision making, relative to social factors. Internationally, transparency in supply chain (TISC) principles lie at the heart of recent legislation such as the UK Modern Slavery Act (2015) and Australia's Modern Slavery Act (2018). The premise is that transparency in large companies' supply chains will commit them to more rigorous investigations and management of modern slavery in global supply chains. However, links between transparency and socially responsible practices are poorly understood; research in multi-tier supply chains is limited and disclosure is often symbolic rather than substantive, with modern slavery statements providing vague commitments that lack details of action undertaken. Hence, the aim of this research programme is to build capacity for developing an understanding of how business decision-makers' behaviours and attitudes impact socially responsible supply chain practices. Ultimately, this will support policy implementation in a manner that prevents the creation of modern slavery victims and the high human costs of survivor recovery and support. The programme will extend relationships that have already been established with key stakeholders in: policy making (UK Home Office), policy implementation (Crown Commercial Service, CCS), large corporations, NGOs (e.g. the Ethical Trading Initiative, ETI), professional associations (Chartered Institute of Procurement and Supply, CIPS) and academia. The research methodology recognises the visually connoted themes in modern slavery, such as transparency. Therefore, photo-elicitation methods will be utilised in conjunction within a participatory action research (PAR) approach. Photo-elicitation will be utilised to bring to the surface the way people see modern slavery both in private and at work. It will establish practitioners' attitudes and actions relating to modern slavery and will reveal participants' perceptions about their ability to influence prevailing issues (agency). The combination with PAR will enable theoretical insights to be assessed in practical contexts. This will be through Government procurement policy and practice and government contractors' supply chain decision makers. The participatory approach will raise the consciousness of all involved in the research programme, helping to identify opportunities and consequences of change to accommodate more socially-oriented supply chain practices. The fellowship will be pivotal in building capacity to extend these relationships and, through research, influencing the development of coordinated changes to policy and practice. The CCS will provide access to participants in selected tier-one suppliers, through which supply chain practices will be investigated. Importantly, the programme will engage and co-create research methods with ETI who work directly with individuals and organisations to combat modern slavery through training and education. My fellowship will engage with RMIT University, Australia (Business and Human Rights Centre), CIPS and the International Slavery Museum as project partners for research co-design, recommendations and dissemination of results. The core outcome of the programme is to contribute to the development of high-quality research on transparency in supply chains that can be used to underpin socially responsible legislation and organisational practice.