Genetic factors and neurobiological markers in relation to ageing, with a specific focus on longevity and dementia

Abstract

The global population is ageing, and by 2050, one in five individuals will be aged 60 years and above. Hereditary advantages, which encompass both genetic and environmental factors, collectively help individuals live longer. This thesis investigated the interrelationships among hereditary factors, brain health, as reflected in the CSF and on structural MRI, and systemic physiology in the context of ageing, utilising a population-based cohort of 70-year-olds followed over six years. Collectively, these studies demonstrated that a family history of longevity is a powerful predictor of healthier ageing. Still, its expression and underlying mechanisms are complex, context-dependent, and often sex-specific. In Study I, we showed that in preclinical Alzheimer's disease, the relationship between CSF biomarkers and brain changes depends on amyloid-β1-42 status, with changes manifesting in deep grey matter structures before cortical thinning (i.e., cortical thickness measures may be less sensitive to the very earliest stages of pathological change). In Study II, we showed that polygenic longevity scores (PGLSs) are not broadly associated with brain integrity or thicker cortices, but rather with a protective effect against cerebrovascular damage, particularly in males, highlighting that vascular health is a critical mechanism linking genetics to both longer life and preserved brain structures. In Study III, we reported that hereditary advantage measured by parental longevity (PL) is associated with a comprehensive neuroprotective phenotype that maintains brain health, including younger-appearing brains, greater structural integrity, and reduced longitudinal atrophy, with greater benefits in males. Finally, in Study IV, we reported that these hereditary advantages (PGLSs or PL) extend beyond maintaining brain health to a multi-system longevity-related profile of healthier inflammatory, neurodegeneration, metabolic, and lipid markers, as well as better childhood and higher current socioeconomic status. In conclusion, the work in this thesis demonstrated that hereditary factors, whether measured by PGLSs or PL, exert a significant influence on ageing trajectories, mostly by promoting vascular health and delaying pathological changes. Still, these effects are highly specific to biological sex and pathological context.