Association of neuroticism with incident dementia, neuroimaging outcomes, and cognitive function

AbstractINTRODUCTIONHigher neuroticism might be associated with dementia risk. Here we investigated modification by genetic predisposition to dementia, mediation by mental health and vascular conditions, neuroimaging outcomes, and cognitive function.METHODSCox proportional‐hazards models were used to assess the association between neuroticism score and incident dementia over up to 15 years in 1,74,164 participants. Cross‐sectional analyses on dementia‐related neuroimaging outcomes and cognitive function were conducted in 39,459 dementia‐free participants.RESULTSHigher neuroticism was associated with an 11% higher risk of incident dementia, especially vascular dementia (15% higher risk), regardless of genetic predisposition to dementia. Mental and vascular conditions mediated the association of neuroticism with all‐cause dementia and vascular dementia. Neuroticism was associated with higher cerebrovascular pathology, lower gray matter volume, and worse function across multiple cognitive domains.DISCUSSIONNeuroticism could represent a risk factor for dementia, and vascular and mental health might drive these associations.Highlights Neuroticism was associated with an increased risk of incident all‐cause dementia, particularly vascular dementia. Associations were not modified by genetic predisposition to dementia. Associations were largely mediated by mental and vascular conditions. Neuroticism was associated with increased cerebrovascular pathology and lower gray matter volume. Neuroticism was associated with worse function across multiple cognitive domains.