Genetic variation associated with human longevity, Alzheimer’s disease risk and severe COVID-19 act through the innate immune system: drivers of inflammageing

Dr Dervis Salih; UK Dementia Research Institute at UCL

Dervis Salih is a Senior Research Associate at the UK Dementia Research Institute at University College London. His research interests focus on understanding the mechanisms by which the innate immune system controls genetic risk for Alzheimer’s disease, ageing and severe COVID-19. Dervis integrates data from human population GWAS with transcriptional networks, and mouse and cell models. Dr Dervis Salih achieved a bachelor's degree in Molecular Genetics at King’s College, University of London, UK. He completed his PhD at the Babraham Institute in Cambridge, investigating insulin-like growth factor signalling. Dervis then performed postdoctoral research at Stanford University in California, studying ageing pathways in the brain using behaviour and electrophysiology.

Introduction Ageing is the primary risk factor for neuroinflammatory conditions, including Alzheimer’s disease (AD), and COVID. However, molecular mechanisms linking chronological age to biological age, and how these underlie AD, are not well understood. The objective of this study was to gain insights into the processes which connect ageing, AD and other neuroinflammatory disorders, by using common human genetic variation associated with human resilience (healthy ageing), AD and other GWAS. Methods Gene-based GWAS data was integrated into preserved co-expression networks associated with age in the brains of C57BL/6J mice and humans (bulk,single-cell and long-read RNA-seq data). Spatial transcriptomics. Human iPSC-microglia culture. Results Genetic variation associated with AD was enriched in both microglial and oligodendrocytic genetic networks, which show increased expression with ageing in the human hippocampus. In contrast, longevity-associated genetic variation was modestly enriched in a single-cell gene network expressed by homeostatic innate immune cells, and involved APOE. Discussion Genetic variation contributing to ageing and AD do not fall on the same genes but may balance different aspects of innate immune function. Our data suggest a hypothesis whereby ageing-related processes alter homeostatic control of the innate immune system affecting lifespan, and genetic variation in age-dependent genes control activated microglial function and myelination tipping some people into AD. The genes driving homeostatic enrichment includeCASP8 and STAT3. The genes we identify likely drive inflammageing, and may aid biomarker design.