AbstractBackgroundNeuroticism, the tendency toward negative mood states, is associated with Alzheimer’s Disease (AD) and tau pathology within entorhinal cortex (EC) in mild cognitive impairment and healthy older adults. However, studies of the link between neuroticism and structural neurodegeneration of EC have been negative. This may result from failure to account for subsyndromal affective symptoms or previous psychiatric history, as neuroticism is closely related to mood conditions that in turn, affect similar brain regions vulnerable to AD. We examined the association between neuroticism and EC volume while accounting for cognition, affective symptoms, and other personality traits in cognitively unimpaired (CU) older adults without history of major psychiatric conditions.Method42 CU adults (age = 71.1 years, 27 females) with normal neuropsychological test performance and no known neurological conditions and current or past psychiatric disorders completed Geriatric Depression Scale, State‐Trait Anxiety Inventory, NEO Five‐Factor Inventory‐3 which assesses neuroticism, openness, conscientiousness, extraversion, and agreeableness, Montreal Cognitive Assessment (MoCA), and structural magnetic resonance imaging of whole brain at 3T. Regression analyses examined the unconditional ability of neuroticism to predict bilateral EC volume, and while considering the potential contribution of cognition (MoCA, California Verbal Learning Test Delayed Recall), affective state, other personality traits, and age, gender, and education. P<.10 was set as the significance threshold for β estimates.ResultIn univariable modelling, neuroticism was predictive of left EC volume (β = ‐17.4, p = .025), explaining 9.8% of its variability [F(1, 40) = 5.45, p = .025]. Neuroticism remained a significant predictor of left EC volume (β = ‐1.9, p = .045) after factoring in demographic, cognitive and affective/personality variables. Additional left EC predictors were extraversion and state anxiety (β = ‐2.61, p = .01; β = 1.71, p = .045 respectively). Neuroticism was not predictive of right EC in univariable or multivariable modelling, but agreeableness emerged as a significant predictor (β = ‐1.68, p = .091).ConclusionNeuroticism was predictive of left EC volume in CU adults without current or past history of psychiatric disorders, independent of cognition, affect, and other personality traits. These findings, which have not been previously reported, extend previous epidemiological evidence of increased AD risk due to neuroticism and suggest the importance of considering the impact of mood symptoms and psychiatric history in this context.