The mediating role of biological age in the impact of mood instability symptoms on neurodegenerative disease and mortality.

BACKGROUND

Accumulating evidence links mood instability to an increased risk of adverse outcomes, yet its relationship with neurodegenerative diseases remains underexplored. This study examines the associations between mood instability symptoms and the risk of neurodegenerative diseases, exploring the mediating role of biological aging.

METHODS

The participants in the UK Biobank without a diagnosed neurological condition at baseline were included. Mood instability symptoms were assessed at two time points: baseline (2006-2010, T1) and the third visit (2014 + , T2), using 13 items of mental symptoms (e.g., "mood goes up and down," "miserable for no reason"). Biological aging was generated by two previously described measures of biological age based on 14 routinely measured clinical biomarkers (PhenoAge, Klemera-Doubal method age). Latent class analysis (LCA) was employed to classify individuals into different psychological clusters. Cox proportional hazard models and mediation analyses were used to examine the associations between mood instability symptoms, biological aging, and adverse health outcomes. The latent transition analysis (LTA) identified latent classes of transition, and multifactor logistic regression was used to examine the sex difference in the probability of transitioning between these latent classes.

RESULTS

Of 185,818 included participants, 51.86% were female. During a median follow-up of 14.6 years, we identified three clusters with distinct mood patterns. Compared to individuals with a pattern of "stable," individuals with severe mood instability symptoms at baseline was significantly associated with an increased risk of all-cause dementia (hazard ratio [HR] = 1.17, 95% CI: 1.02-1.35), Parkinson's disease (HR = 1.47, 95% CI: 1.21-1.77), and all-cause mortality (HR = 1.07, 95% CI: 1.01-1.14). Accelerated biological aging was also linked to a higher risk of both dementia and Parkinson's disease. Mediation analyses revealed that biological aging partially mediated the association between severe mood instability symptoms and neurodegenerative diseases, as well as mortality (ranging from 0.78% to 13.6%). Notably, females had a higher risk of transitioning to more severe groups over time.

CONCLUSIONS

These findings underscore the critical need to focus on severe mood instability symptoms in early intervention strategies to reduce neurodegenerative disease risk, particularly by focusing on emotional well-being in females.