Peripheral GDF15 as an early biomarker for brain disorders: A large prospective cohort study.

BACKGROUND: Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine involved in metabolic and inflammatory pathways. We examined the associations of plasma GDF15 with incident brain disorders and explored potential mediating pathways and causality. METHODS: UK Biobank participants were followed for a median of 14 years. Plasma GDF15 was measured at baseline. Cox proportional hazards models assessed associations with incident brain disorders, including all-cause dementia (ACD), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, depression, sleep disorders, stroke, and epilepsy. Mediation analyses evaluated biochemical and hematological pathways, and one-sample Mendelian randomization (MR) was used to assess potential causal effects. RESULTS: Higher GDF15 levels were associated with increased risks of overall brain disorders and all examined subtypes. In continuous analyses (per 1-unit increase in log2-transformed GDF15), hazard ratios (95% CIs) were 1.54 (1.48-1.60) for overall brain disorders, 1.98 (1.80-2.17) for ACD, 1.84 (1.60-2.10) for AD, 1.37 (1.18-1.59) for PD, 1.26 (1.16-1.37) for anxiety, 1.38 (1.29-1.49) for depression, 1.40 (1.26-1.55) for sleep disorders, 1.92 (1.81-2.05) for stroke, and 1.71 (1.46-2.01) for epilepsy (all P < 0.001). Lipid- and inflammation-related markers appeared to partially mediate these associations. High-density lipoprotein cholesterol (HDL-C) accounted for an estimated 7.51% of the association with depression and 11.47% with sleep disorders, while neutrophil count showed relatively larger mediation estimates across multiple outcomes. MR analyses did not support a direct causal effect of GDF15. CONCLUSION: Plasma GDF15 is associated with a broad range of incident brain disorders and may act partly through lipid- and inflammation-related pathways, particularly HDL-C and neutrophil count.