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Potential Mediating Role of Polygenic Hazard Score in the Association Between Neurofilament Light Chain and Default Mode Network Connectivity Across the Alzheimer's Disease Continuum Publisher



Saberian P1 ; Nasiri H2 ; Kaffashian F3 ; Nasiriansari P4 ; Nasab FN5 ; Mehrvarz N6 ; Talebizadeh F7 ; Shakeri S8 ; Mayeli M9
Authors
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Authors Affiliations
  1. 1. Student Research Committee, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
  2. 2. Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
  3. 3. Mazandaran University of Medical Sciences, Mazandaran, Iran
  4. 4. Biology Department, University of Mazandaran, Mazandaran, Iran
  5. 5. Lorestan University of Medical Sciences, Lorestan, Iran
  6. 6. Islamic Azad University Medical Branch of Tehran, Tehran, Iran
  7. 7. Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
  8. 8. Department of medical genetics, School of medicine, Shiraz university of medical sciences, Shiraz, Iran
  9. 9. School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Source: IBRO Neuroscience Reports Published:2025


Abstract

Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder marked by progressive cognitive decline and disrupted brain network connectivity, particularly within the default mode network (DMN). Neurofilament light chain (NfL) serves as a biomarker for axonal injury, but the role of genetic predisposition, assessed via the Polygenic Hazard Score (PHS), in mediating the association between plasma NfL and DMN connectivity remains unclear. This study investigates whether PHS mediates the association between plasma NfL levels and DMN connectivity in individuals across different cognitive stages, including cognitively normal (CN), mild cognitive impairment (MCI), and AD. Methods: Data were extracted from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Plasma NfL concentrations were measured using the Simoa assay, and resting-state fMRI (rs-fMRI), assessed DMN connectivity. The cohort included 102 participants (nCN=28, nMCI=52, and nAD=22). Partial correlation analyses and mediation models were performed, adjusting for age and gender. Statistical significance was set at p < 0.05, after corrections for multiple comparisons. Results: Plasma NfL levels were significantly higher in AD group compared to CN and MCI groups (p = 0.030). DMN connectivity showed substantial declines in the AD group, particularly in the posterior and ventral regions. Significant negative correlations were observed between plasma NfL and ventral DMN connectivity in AD. However, mediation analysis indicated no significant indirect effect of PHS, suggesting that genetic risk does not mediate the plasma NfL-DMN association. Conclusion: These findings suggest that elevated plasma NfL levels are associated with disrupted ventral DMN connectivity in AD, reflecting neurodegeneration-related network dysfunction. However, the lack of a mediating effect by PHS indicates that this relationship is likely independent of genetic risk burden. Clinical Trial Number: not applicable. © 2025 The Authors
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