Investigating the Causal Relationship between Neuroticism and Alzheimer's Disease Using Mendelian Randomization and the Mediating Role of Modifiable Risk Factors

Neuroticism, a personality trait characterized by the predisposition to experience intense and frequent negative emotions, has been associated with an increased risk of Alzheimer's disease (AD). However, the mechanisms underlying this association remain unclear. Our study investigated two potential pathways: (1) whether the relationship between neuroticism and AD is causal, and (2) whether it is mediated by health and behavioral factors associated with both neuroticism and AD risk. To assess causality, a two-sample Mendelian randomization (MR) was employed using publicly available genome-wide association studies (GWAS) for neuroticism (Nagel et al., 2018) and AD (Bellenguez et al., 2022). Mediation analysis was conducted in a subset of UK Biobank participants aged 60 and older, including 121,825 controls (mean age = 63.9 {+/-} 2.81; 61,993 females or 50.9%) and 1,277 individuals with AD (mean age = 65.6 {+/-} 2.71; 628 females or 49.2%). All participants had complete data on neuroticism and the potential mediators. MR analysis suggested that the neuroticism-AD relationship is unlikely to be causal. However, depression ({beta}=0.048, p=3x10-4), hypertension ({beta}=0.005, p=2x10-4), and alcohol consumption ({beta}=0.001, p=1x10-5) were identified as significant mediators of the relationship between higher neuroticism and increased AD risk. Overall, the association between neuroticism and AD may be largely explained by modifiable health and behavioral factors rather than a direct causal effect. A better understanding of these mediating pathways may inform targeted prevention and therapeutic strategies to reduce AD risk.