¹University Hospital of Psychiatry Zurich, Department of Adult Psychiatry and Psychotherapy, Zurich, Switzerland

Background: Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are blood-based markers of neuroaxonal injury and astroglial activation, respectively. While established in neurology, their relevance in psychiatry remains unclear.

Aims & Objectives: To investigate the associations between circulating markers of neuroaxonal and astroglial structural integrity and psychiatric disorders in older adults, and between these markers and substance use in younger adults.

Method: We analyzed blood NfL and GFAP in UK Biobank (ages 40–65) and the Zurich z-proso cohort (ages 20–21), applying normative modeling across age and sex, clinical variables (UK Biobank), and propensity scores from multimodal substance use assessments combined with structural MRI (z-proso).

Results: In UK Biobank, NfL was modestly elevated in affective disorders but not in psychotic or anxiety disorders, with larger increases in neurological conditions. In z-proso, both markers were partially associated with polysubstance use and with structural brain alterations.

Discussion & Conclusions: Across the lifespan, NfL and, to a lesser extent, GFAP capture neuroaxonal and astroglial processes relevant to psychiatric vulnerability and substance use, supporting their use as scalable biomarkers for population-level studies of brain plasticity and mental health.