ssociation between neuroticism and brain-wide structural outcomes: Mediation by vascular and mental conditions.

BACKGROUND: Neuroticism, a personality trait linked to both cardiovascular and psychiatric disorders, has been associated with cognitive decline and increased dementia risk, though the underlying neural mechanisms remain unclear. Mapping its relationship with brain structure could provide valuable insights into neural pathways and targets for early intervention. METHODS: We examined brain-wide associations between neuroticism and structural neuroimaging metrics derived from T1-, T2-weighted, and diffusion MRI in 36,901 dementia-free UK Biobank participants. Bonferroni-significant associations underwent bidirectional two-sample Mendelian randomization to evaluate the evidence for a causal relationship. Given that neuroticism is generally stable across adulthood and challenging to modify, we assessed whether these associations were mediated by health conditions (depression, anxiety, hypertension, ischemic heart disease [IHD], and diabetes) that are both consequences of neuroticism and known risk factors for dementia, and also modifiable through widely available and efficacious therapeutic interventions. RESULTS: Higher neuroticism was found to be associated with reduced grey matter volumes in the frontal and limbic regions, as well as widespread differences in white matter microstructure, particularly in thalamic radiations. Genetic analyses supported a potential causal effect of neuroticism on increased diffusivity in thalamic radiations. Hypertension mediated the associations between neuroticism and both grey and white matter measures, while depression and anxiety primarily mediated associations with white matter microstructure. Contributions from IHD and diabetes were minimal. CONCLUSIONS: Neuroticism is linked to widespread structural brain differences that contribute to poorer brain health, and targeting vascular and mental health may help mitigate its impact.