多基因危险评分在阿尔茨海默病连续体中神经丝轻链和默认模式网络连接的关联中的潜在中介作用

IF 2.9 Q3 NEUROSCIENCES

IBRO Neuroscience Reports Pub Date : 2025-05-01 DOI:10.1016/j.ibneur.2025.04.018

Parsa Saberian , Hamide Nasiri , Fatemeh Kaffashian , Parisa Nasiriansari , Fatemeh Nazari Nasab , Niusha Mehrvarz , Fatemeh Talebizadeh , Shayan Shakeri , Mahsa Mayeli , for the Alzheimer’s Disease Neuroimaging Initiative

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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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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. 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引用次数: 0

摘要

阿尔茨海默病（AD）是一种复杂的神经退行性疾病，其特征是进行性认知能力下降和大脑网络连接中断，特别是在默认模式网络（DMN）内。神经丝轻链（NfL）是轴突损伤的生物标志物，但通过多基因危险评分（PHS）评估的遗传易感性在介导血浆NfL和DMN连通性之间的关联中的作用尚不清楚。本研究探讨了PHS是否介导不同认知阶段个体血浆NfL水平和DMN连通性之间的关联，包括认知正常（CN）、轻度认知障碍（MCI）和AD。方法数据来自阿尔茨海默病神经影像学倡议（ADNI）。使用Simoa法测量血浆NfL浓度，静息状态fMRI （rs-fMRI）评估DMN连通性。该队列包括102名参与者（nCN=28, nMCI=52, nAD=22）。进行偏相关分析和中介模型，调整年龄和性别。经多次比较校正后，p <； 0.05具有统计学意义。结果AD组血浆NfL水平明显高于CN和MCI组（p = 0.030）。AD组DMN连通性明显下降，特别是在后部和腹侧区域。血浆NfL与AD患者腹侧DMN连通性呈显著负相关。然而，中介分析显示小灵通没有显著的间接影响，表明遗传风险不介导血浆NfL-DMN关联。结论血浆NfL水平升高与AD患者腹侧DMN连通性中断有关，反映了神经退行性相关网络功能障碍。然而，小灵通缺乏中介作用，表明这种关系可能独立于遗传风险负担。临床试验编号不适用。

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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

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.