Luan Ying, Zheng Lukai, Denecke Jannis, Dehsarvi Amir, Roemer-Cassiano Sebastian N, Dewenter Anna, Steward Anna, Shcherbinin Sergey, Svaldi Diana Otero, Kotari Vikas, Higgins Ixavier Alonzo, Pontecorvo Michael J, Valentim Carolina, Schnabel Julia A, Casale Francesco Paolo, Dyrba Martin, Teipel Stefan, Franzmeier Nicolai, Ewers Michael
Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University (LMU), Munich, Germany.
Alzheimers Dement. 2025 May;21(5):e70170. doi: 10.1002/alz.70170.
In Alzheimer's disease (AD), fibrillar tau gradually progresses from initial seed to larger brain area. However, those brain properties underlying the region-dependent susceptibility to tau accumulation remain unclear.
We constructed multimodal spatial gradients to characterize molecular properties and connectomic architecture. A predictive model for regional tau deposition was developed by integrating embeddings in the principal gradients of global connectome gradients with gene expression, neurotransmitters, myelin, and amyloid-beta. The model was trained on amyloid-beta-positive participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) and externally validated in independent datasets.
The combination of gradients explained up to 77.7% of cross-sectional and 77.3% of longitudinal inter-regional variance of tau deposition. Gene set enrichment analysis of a major gene expression gradient points to synaptic transmission to confer increased susceptibility to tau.
Our findings reveal a spatially heterogeneous molecular landscape shaping regional susceptibility to tau deposition, presenting a powerful system-level explanatory model of tau pathology in AD.
Spatial gradients of fundamental molecular brain properties associated with tau pathology. The explanatory power showed high consistency across studies. Genetic analyses suggested that synapse expression plays a vital role in tau accumulation.
在阿尔茨海默病（AD）中，纤维状tau蛋白从初始种子逐渐扩散至更大的脑区。然而，tau蛋白积累的区域依赖性易感性背后的脑特性仍不清楚。
我们构建了多模态空间梯度来表征分子特性和连接组结构。通过将全局连接组梯度的主要梯度中的嵌入与基因表达、神经递质、髓磷脂和淀粉样β蛋白整合，开发了区域tau蛋白沉积的预测模型。该模型在阿尔茨海默病神经成像倡议（ADNI）的淀粉样β蛋白阳性参与者中进行训练，并在独立数据集中进行外部验证。
梯度组合解释了高达77.7%的tau蛋白沉积横断面方差和77.3%的纵向区域间方差。对一个主要基因表达梯度的基因集富集分析表明，突触传递会增加对tau蛋白的易感性。
我们的研究结果揭示了一种塑造tau蛋白沉积区域易感性的空间异质性分子景观，为AD中的tau蛋白病理学提供了一个强大的系统水平解释模型。
与tau蛋白病理学相关的基本分子脑特性的空间梯度。解释力在各项研究中显示出高度一致性。遗传分析表明，突触表达在tau蛋白积累中起着至关重要的作用。
