Serum NfL and GFAP levels and their association with anxiety-depression in Alzheimer’s disease patients: A clinical retrospective study

Abstract

BACKGROUND

Anxiety-depression symptoms frequently coexist and greatly shape the life quality and disease course of individuals with Alzheimer’s disease (AD). While serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), as well as neuronal and astrocytic injury markers may serve as relevant predictors in the development of such psychiatric symptoms among AD patients, the underlying mechanisms governing their combined predictive capacity remain poorly understood.

AIM

To determine the relationship of serum NfL and GFAP concentrations with anxiety-depression symptoms in AD patients, as well as evaluate the added predictive value of these two biomarkers for high-risk individuals.

METHODS

We retrospectively analyzed clinical data from 270 patients with confirmed AD who were admitted to the neurology unit of our hospital from January 2022 until December of 2024. Participants were divided according to Hospital Anxiety and Depression Scale assessments as an anxiety-depression cohort (n = 122), or no such symptoms (control cohort, n = 148). Single-molecule array technology was used to quantify serum NfL, while enzyme-linked immunosorbent assay was used to measure serum GFAP. Age-stratified analyses were performed to examine the association of age groups and anxiety-depression prevalence. Using logistic regression to isolate risk factors, receiver operating characteristics curves were then used to quantify the model discriminative power.

RESULTS

Out of 270 enrolled patients (mean old: 73.1 ± 8.3 years; male proportion: 46.3%), we described a later encounter satisfaction in both anxiety and/or depressive symptoms which had been recognized in 122 individuals (45.2%). Using the log-transformed NfL and GFAP values, patients with anxiety-depression exhibited significantly higher levels of both proteins vs controls (32.8 ± 8.6 pg/mL vs 21.6 ± 6.4 pg/mL for NfL; μ = ± SD: 187.2 ± 43.2 pg/mL vs 127.8 ± 34.8 pg/mL for GFAP). Age-stratified analysis demonstrated a nonrandomized association between older age and anxiety-depression incidence (55-64: 32.8%, 65-74: 44.0%, 75-89: 54.5%; P for trend = 0.008). Two independent predictors based on multivariate analysis were NfL elevation [odds ratio = 3.28; 95% confidence interval (CI): 1.64-6.56; P = 0.001] and GFAP elevation (odds ratio = 2.92; 95%CI: 1.48-5.76; P = 0.002). The integrated biomarker model demonstrated a superior discriminative performance (area under the curve = 0.882; 95%CI: 0.836-0.928) with 81.1% sensitivity and 84.5% specificity as compared to any individual marker alone (P < 0.001).

CONCLUSION

Serum NfL and GFAP together would be particularly excellent predictors of anxiety and depression in people with AD. Age-stratified analysis shows an independent association between increasing age and vulnerability to anxiety-depression. Our composite biomarker panel provides a useful, robust and convenient means of identifying early AD patients at greater risk of anxiety and depression.

Keywords: Alzheimer’s disease; Anxiety; Depression; Neurofilament light chain; Glial fibrillary acidic protein; Biomarkers; Age stratification; Retrospective analysis

Core Tip: Anxiety and depression are common neuropsychiatric disorders that negatively influence prognosis and quality of life in patients with Alzheimer’s disease. Results from this study show that the combination of serum neuroaxonal damage marker and astrocytic activation marker, not the single markers, have improved prognostic value for anxiety and depression. Age-stratified analysis provides further evidence of a strong age-dependent gradient in anxiety-depression prevalence These findings highlight the role of thorough biomarker assessment in combination with age-related risk stratification in everyday clinical practice to identify and treat at-risk patients better and earlier for Alzheimer’s disease.