Gong Zhaoyuan, Laporte John P, Guo Alexander Y, Bae Jonghyun, Fox Noam Y, de Rouen Angelique, Zhang Nathan, Taranath Aaliya, de Cabo Rafael, Egan Josephine M, Ferrucci Luigi, Bouhrara Mustapha
National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
medRxiv. 2025 Aug 15:2025.08.13.25333630. doi: 10.1101/2025.08.13.25333630.
With global dementia rates rising sharply, there is an urgent need for sensitive biomarkers to detect cognitive changes and predict dementia risk. White matter degeneration, especially axonal loss, is increasingly recognized as an early hallmark of Alzheimer's disease (AD), but its temporal trajectory and its relationship with cognition have not been established. We utilized a novel MRI-derived Axonal Density Index (ADI) to longitudinally investigate axonal degeneration and cognitive decline in the ADNI cohort. Linear mixed-effects models showed cognitively impaired individuals had lower baseline ADI and faster axonal degeneration compared to cognitively normal subjects. In cognitively impaired individuals, higher baseline ADI predicted slower prospective cognitive deterioration and lower dementia risk, while greater longitudinal ADI declines correlated with cognitive worsening and increased dementia risk. Notably, ADI outperformed cerebrospinal fluid biomarkers of AD pathology in predicting cognitive outcomes. Our original findings position axonal degeneration as an early AD feature and ADI as a promising biomarker for early detection, disease phenotyping and monitoring, and intervention targets.
随着全球痴呆症发病率急剧上升，迫切需要灵敏的生物标志物来检测认知变化并预测痴呆症风险。白质退化，尤其是轴突损失，越来越被认为是阿尔茨海默病（AD）的早期标志，但其时间轨迹以及与认知的关系尚未明确。我们利用一种新的磁共振成像衍生轴突密度指数（ADI）对阿尔茨海默病神经成像计划（ADNI）队列中的轴突退化和认知衰退进行纵向研究。线性混合效应模型显示，与认知正常的受试者相比，认知受损个体的基线ADI较低，轴突退化更快。在认知受损个体中，较高的基线ADI预示着未来认知衰退较慢且痴呆症风险较低，而纵向ADI下降幅度越大与认知恶化及痴呆症风险增加相关。值得注意的是，在预测认知结果方面，ADI优于AD病理学的脑脊液生物标志物。我们的原始研究结果将轴突退化定位为AD的早期特征，并将ADI定位为用于早期检测、疾病表型分析和监测以及干预靶点的有前景的生物标志物。
