Team EMERALD
Dementia Frontiers Fund
Epigenomic Mechanisms of Extreme Resilience and APOE Liability in Dementia.
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Led by
Dr Sarah Marzi (King’s College London), Associate Professor Henne Holstege (Vrije Universiteit Amsterdam/ KU Leuven) and Dr Alexi Nott (Imperial College London)
Research question
Locations
UK, The Netherlands and Belgium
Research institutions
4
Project summary
EMERALD seeks to understand the biological mechanisms that enable some individuals to remain cognitively healthy despite advanced age, substantial Alzheimer’s disease pathology and genetic risk. Rather than focusing on the causes of disease, the programme investigates the mechanisms of resilience, using cognitively healthy centenarians as a natural model of successful brain ageing.
The central hypothesis is that resilience emerges through the interaction of protective genetic architectures, cell-type-specific epigenomic regulation and acquired somatic variation within the immune system, which together determine whether pathological changes translate into clinical dementia.
The project will leverage the unique CENTURY-X50 cohort, comprising highly characterised centenarian brains representing the biological extremes of resistance, resilience and dementia.
Using fluorescence-activated nuclear sorting, the team will generate cell-type-specific epigenomic profiles of neurons, microglia, astrocytes and oligodendrocytes, examining chromatin accessibility and regulatory activity linked to protective and risk-associated genetic variants.
The researchers will also investigate the influence of clonal haematopoiesis and acquired somatic mutations on brain immune cell states, integrating these findings with digital neuropathology, spatial multi-omics and clinical data. Mechanistic validation will be undertaken in human iPSC-derived microglial models, focusing on regulatory pathways implicated in resilience, including vitamin D receptor signalling.
By identifying the molecular programmes that protect against cognitive decline, EMERALD aims to establish a foundation for new biomarkers, preventative strategies and therapeutic approaches that promote healthy brain ageing and resistance to dementia.
Plain English summary
Some people remain mentally healthy into their 90s and beyond, even though their brains show changes normally associated with Alzheimer’s disease.
This project will investigate what protects these individuals from developing dementia, focusing on the biological processes that support healthy brain ageing. By understanding the mechanisms behind this resilience, the researchers hope to identify new ways to prevent, delay or treat dementia.
Potential future impact
This research could uncover the biological and epigenetic mechanisms that help some people remain cognitively healthy despite having Alzheimer’s-related brain changes.
By identifying the pathways that promote resilience, the project may reveal new targets for therapies aimed at preserving memory and cognition in later life.
The findings could also improve understanding of when protective and harmful changes emerge during ageing, informing strategies for prevention earlier in life.
In the longer term, studies in human brain cell models could help determine whether existing medicines can activate these protective mechanisms, while the identification of resilience-related biomarkers could support earlier detection of vulnerability or protection before symptoms develop.
Ultimately, the work has the potential to shift dementia research towards understanding and promoting healthy brain ageing, rather than focusing solely on disease processes.