2026 ECNP Congress

PS03-3046

The relationship between serum FGF-21 and GDF-15 levels and cognitive functioning in a healthy population

Yağmur Darben Azarsız — A. Civan Kahve, E.S. Ahi Ustun, A. Uzdogan, N. Ayaz Naycı, E. Goka, H. Kaya · Department of Psychiatry- Barıs Mental and Neurologıcal Dıseases Hospital, Psychiatry, Lefkoşa, Cyprus

2026 ECNP Congress

Background

Cognitive functioning is highly dependent on efficient cellular energy metabolism, and mitochondrial dysfunction has been increasingly implicated in cognitive processes through its effects on cellular stress responses and metabolic balance (1, 2). FGF21 and GDF15 are stress-responsive biomarkers involved in mitochondrial function and metabolic homeostasis, and accumulating evidence suggests that they may also have neurobiological significance (2, 3). Experimental studies suggest that FGF21 may exert neuroprotective effects and contribute to cognitive functioning by improving synaptic plasticity and mitochondrial activity (1). Elevated GDF15 levels, on the other hand, have been associated with reduced gray matter volumes and poorer cognitive performance in several domains (4). However, the relationship between serum FGF21 and GDF15 levels and cognitive functioning in healthy individuals remains poorly understood. Therefore, this study aimed to investigate the association between serum FGF21 and GDF15 levels and cognitive performance in a healthy population.

Methods

This cross-sectional study included 87 healthy adults with no history of psychiatric, neurological, or major medical illness. The sample comprised 40 women (46%) and 47 men (54%), with a mean age of 38.72±10.07 years and a mean education duration of 12.56±4.02 years. Serum FGF21 and GDF15 levels were measured using standardized laboratory procedures. Cognitive performance was assessed using the Wisconsin Card Sorting Test (WCST), Stroop Test, and Trail Making Test (TMT), which collectively evaluate executive functioning, attention, and processing speed. In healthy controls, mean neuropsychological test scores were 5.08±1.47 for WCST completed categories, 19.69±14.13 for total perseverative responses, 26.17±9.16 seconds for Stroop Test Part 5 total time, 31.28±12.25 seconds for TMT Part A, and 95.98±51 seconds for TMT Part B. Data distribution was assessed prior to analysis, and Spearman correlation analyses were performed to examine the associations between biomarker levels and cognitive measures.

Results

Serum FGF21 levels were not significantly associated with WCST completed categories (r=-0.099, p=0.361), total perseverative responses (r=0.038, p=0.725), Stroop Test Part 5 total time (r=0.077, p=0.479), TMT Part A time (r=0.006, p=0.958), or TMT Part B time (r=0.117, p=0.280). In contrast, higher GDF15 levels were significantly associated with poorer cognitive performance, including fewer WCST completed categories (r=-0.309, p=0.004), more total perseverative responses (r=0.267, p=0.012), longer Stroop Test Part 5 total time (r=0.219, p=0.042), longer TMT Part A duration (r=0.255, p=0.017), and longer TMT Part B duration (r=0.230, p=0.032). These associations were consistent across multiple domains of cognitive functioning, particularly executive processes and processing speed, suggesting a potential pattern linking higher GDF15 levels to subtle cognitive inefficiencies even within a healthy sample.

Conclusions

These findings suggest that higher serum GDF15 levels may be related to relatively lower performance in executive functioning, attention, and processing speed, even among healthy individuals. In contrast, FGF21 did not show a clear association with cognitive performance in this population. Thus, GDF15 may be a potentially more sensitive biomarker of subtle cognitive variability in non-clinical samples. However, further studies with larger samples and longitudinal designs are needed to better clarify the mechanisms underlying these associations.

References

  1. Sa-Nguanmoo P, Tanajak P, Kerdphoo S, Satjaritanun P, Wang X, Liang G, et al. FGF21 improves cognition by restored synaptic plasticity, dendritic spine density, brain mitochondrial function and cell apoptosis in obese-insulin resistant male rats. Hormones and behavior. 2016;85:86-95.
  2. Fujita Y, Taniguchi Y, Shinkai S, Tanaka M, Ito M. Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age‐related disorders. Geriatrics & gerontology international. 2016;16:17-29.
  3. Fisher FM, Maratos-Flier E. Understanding the physiology of FGF21. Annual review of physiology. 2016;78(1):223-41.
  4. Jiang J, Wen W, Brown DA, Crawford J, Thalamuthu A, Smith E, et al. The relationship of serum macrophage inhibitory cytokine–1 levels with Gray matter volumes in community-dwelling older individuals. PLoS One. 2015;10(4):e0123399.