Reduced Plasma Aβ Peptides but Stable NfL and GFAP in Major Depressive Disorder

Major depressive disorder (MDD) has been associated with an increased risk of cognitive decline and neurodegenerative disorders like Alzheimer's disease (AD), prompting interest in peripheral biomarkers related to amyloid metabolism as well as neuroaxonal and astroglial injury. However, evidence regarding circulating markers in MDD remains inconsistent. In this cross-sectional study, we simultaneously assessed plasma levels of amyloid-β peptides (Aβ40 and Aβ42), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in MDD patients and healthy controls (HC) using ultrasensitive single-molecule array (SIMOA) technology. Associations with clinical and cognitive scales were examined. Plasma concentrations of Aβ40 and Aβ42 were significantly lower in MDD patients, whereas no group differences were observed for NfL and GFAP, after correcting for age and sex. However, both Aβ peptides were not significantly associated with depressive symptom severity, whereas the Aβ42/Aβ40 ratio was negatively associated with anhedonia. NfL and GFAP levels were primarily influenced by age. In the absence of a reduced Aβ42/Aβ40 ratio, these findings suggest that reduced plasma Aβ levels in MDD may reflect systemic or metabolic factors associated with MDD, including lifestyle or treatment-related effects. Therefore, these findings should be interpreted with caution and further examined in longitudinal studies to prevent potential confounding factors.