Salzmann, Antoine Emile; (2023) The role of the insulin-like growth factor pathway on later-life brain health. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The Insulin-like Growth Factor (IGF)-pathway is involved in numerous biological processes, including some key to central nervous system (CNS) development and maintenance. However, the associations between circulating IGF-pathway protein concentrations and ageing brain health, and whether these are causal, remain unclear. Data collected from the National Survey of Health and Development (NSHD; n = 1,762) and UK Biobank (n = 502,411) were analysed to investigate the associations of IGF-pathway proteins with cognitive function, neuroimaging measures of brain atrophy and neurovascular health, and dementia incidence. Analytical methods included a comprehensive combination of observational epidemiology (linear and logistic regression; time-to-event analysis) and Mendelian randomisation (MR) to investigate causality. In the NSHD (age range: 53 – 73 years) and its neuroimaging sub-study, Insight-46, increased measures of IGF-pathway parameters (IGF-I, IGF-II, IGFBP-3) were associated with favourable cognitive outcomes, and some evidence of less neurovascular damage (Chapter 3). These observational findings were generally consistent in the UK Biobank (age range: 40 – 82 years) where higher IGF-I was associated with generally better performance on cognitive assessments, lower brain atrophy and neurovascular damage, and reduced risk of incident dementia (Chapter 4). In both cohorts, the magnitude of estimates varied across age groups, with association estimates for all-cause dementia models changing direction in the oldest age group (> 65 years) in the UK Biobank. These findings were, however, not reproduced in MR analyses which found no consistent associations between genetically instrumented IGF-I or IGFBP-3 and any of the brain health outcomes examined (Chapter 5). In summary, findings from observational analyses suggest generally beneficial associations between IGF-pathway proteins and brain health outcomes, but these may not be causal. Future research should aim to understand the reasons for these conflicting findings before considering interventions on the IGF-pathway as a treatment for declining brain health.

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