Abstract

AbstractBackgroundPrior studies have shown that certain personality traits are associated with differences in aging‐related cognitive decline and incidence of Alzheimer’s disease (AD). Neuroticism, proneness to pscyhological distress, worsens cognitive decline while conscientiousness is protective. However, the molecular composition of these personality traits and the series of molecular events that lead from personality traits to AD in the brain is unknown.MethodWe examined data from 1419 participants in one of two longitudinal studies of cognitive aging with prospectively collected brains at autopsy: the Religious Order Study and the Rush Memory & Aging Project (ROSMAP). We accessed RNA sequence data (>13,000 genes) from the dorsolateral prefrontal cortex (DLPFC); linear regression adjusting for age, sex, and education. We performed a mediation analysis to assess whether certain modules mediate the association of neuroticism to cognitive decline.ResultWe first confirmed that neuroticism contributes to accelerated cognitive decline and AD onset (p=6.75x10‐7) while conscientiousnessis protective (p=4.34x10‐4). We then evaluated the 6 gene modules previously associated with cognitive decline (p<0.001) and found that three of them displayed some association with neuroticism (p<0.05). Mediation modeling suggests that these three modules of co‐expressed genes are altered by in individual’s with greater neuroticism. Neurotic is associated with higher m7 which in turn is related to cognitive decline (p=0.008) than its direct causal effect on cognitive decline which is not mediated through m7 (p=0.042).ConclusionWe demonstrate neuroticism is associated widespread differences in RNA profiles and that these differences contribute to the onset of AD. Although results need further investigation, they identify a new gene signature that could be used to develop new therapies that minimize the risk of AD in individuals with a neurotic personality.

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