Association between baseline circulating FGF21 Levels and Depressive Symptoms at follow up in Older Adults: Evidence from the FRASNET Cohort

Description

Rationale: to evaluate Fibroblast Growth Factor 21 (FGF21) as a possible biomarkers for depressive symtopms in elderly. FGF21 is a stress-induced hepatokine involved in inflammation and neuroendocrine regulation, processes implicated in depression. Methods: We investigated the association between FGF21 and depressive symptoms in community-dwelling older adults. Data were obtained from 52 older individuals (median age 70; 61.5% women) within the FRASNET cohort who underwent longitudinal assessments (2017 for baseline –2024 for follow up). Depressive symptoms were evaluated using the 15-item Geriatric Depression Scale (GDS). Regression models adjusted for age, sex, and body mass index were used to assess associations between FGF21 and depressive symptoms. Results: Circulating FGF21 levels declined significantly over time (p = 0.03) but remained higher in individuals with depressive symptoms at both baseline and follow-up. Elevated baseline FGF21 predicted higher GDS scores at follow-up (adjusted B = 0.003, 95% CI 0.000–0.006, p = 0.049). Discriminatory performance for elevated depressive symptoms was modest (AUC = 0.66). Conclusions: Higher baseline FGF21 levels were associated with greater depressive symptom burden at follow-up. These findings should be considered preliminary and hypothesis-generating. Further studies using diagnostic outcomes and larger samples are warranted.

Steps to reproduce

The Frailty and Sarcopenia Network (FRASNET) is a multicenter observational cohort including community-dwelling and institutionalized older adults. The study was approved by the San Raffaele Scientific Institute (24/INT/2017), and all participants provided written informed consent. Recruitment occurred between April 2017 and October 2020. Participants were eligible if they were ≥65 years old, able to walk >500 m without assistance, and had a life expectancy >6 months. Exclusion criteria included severe cognitive impairment (Mini-Mental State Examination [MMSE] <18), inability to provide informed consent, or severe health conditions such as uncontrolled hypertension, recent fractures of the upper or lower extremities, or myocardial infarction within the previous year. Between 2023 and 2024, participants were re-contacted by telephone to confirm survival status and assess willingness to attend follow-up visits. Eligible participants were invited for in-person evaluations. In addition to the geriatric assessments performed between 2017 and 2020, follow-up visits included a comprehensive evaluation of functional status, frailty, nutritional status, sarcopenia, and mood. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15), a screening tool for depressive symptoms in older adults. Consistent with validation studies, a score ≥5 indicated clinically relevant depressive symptoms. Aging-related biomarkers relevant to multimorbidity, frailty, and disability were selected through a Delphi consensus process involving clinicians and biologists from several Italian universities. Among candidate biomarkers, FGF21 was selected. FGF21 concentrations were measured using the ELLA™ automated immunoassay platform (Bio-Techne, San Jose, CA, USA) on blood samples collected and biobanked during the original FRASNET study (2017–2020) and follow-up visits (2023–2024). Descriptive statistics summarized baseline characteristics. Continuous variables were expressed as mean ± SD or median (IQR), and categorical variables as frequencies (%). Changes between baseline and follow-up were assessed using paired t-tests or Wilcoxon signed-rank tests and χ² tests for categorical variables. Differences in FGF21 levels by sex and depressive symptom status were evaluated using the Mann–Whitney U test. Associations between FGF21 and depressive symptoms were explored using linear regression models adjusted for age, sex, and BMI. ROC analysis using the GDS-15 cut-off (≥5) evaluated the ability of FGF21 to discriminate individuals with depressive symptoms. Optimal thresholds were identified using the Youden index. Statistical analyses were performed using SPSS version 25.

Institutions

• IRCCS Ospedale San Raffaele

  Lombardy, Milan

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Funders

• European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS.

  Grant ID: PNRR-MAD-2022-12376672, CUP C43C22001310007

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