Li Yanxiao, Wang Xiuying, Ge Qi, Graeber Manuel B, Yan Shaozhen, Li Jian, Li Shuyu, Gu Wenjian, Hu Shuo, Benzinger Tammie L S, Lu Jie, Zhou Yun
School of Computer Science, The University of Sydney, Sydney, NSW, 2006, Australia.
Central Research Institute, United Imaging Healthcare Group Co., Ltd, Shanghai, 201807, China.
EJNMMI Phys. 2025 Jun 9;12(1):55. doi: 10.1186/s40658-025-00761-4.
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder in which tau neurofibrillary tangles are a pathological hallmark closely associated with cognitive dysfunction and neurodegeneration. In this study, we used brain tau data to investigate AD heterogeneity by identifying and characterizing the subpopulations among patients. We included 615 cognitively normal and 159 AD brain F-flortaucipr PET scans, along with T1-weighted MRI from the Alzheimer Disease Neuroimaging Initiative database. A three dimensional-convolutional neural network model was employed for AD detection using standardized uptake value ratio (SUVR) images. The model-derived saliency maps were generated and employed as informative image features for clustering AD participants. Among the identified subpopulations, statistical analysis of demographics, neuropsychological measures, and SUVR were compared. Correlations between neuropsychological measures and regional SUVRs were assessed. A generalized linear model was utilized to investigate the sex and APOE ε4 interaction effect on regional SUVRs.
Two distinct subpopulations of AD patients were revealed, denoted as S and S. Compared to the S group, the S group exhibited a significantly higher global tau burden in the brain, but both groups showed similar cognition distribution levels. In the S group, the associations between the neuropsychological measurements and regional tau deposition were weakened. Moreover, a significant interaction effect of sex and APOE ε4 on tau deposition was observed in the S group, but no such effect was found in the S group.
Our results suggest that tau tangles, as shown by SUVR, continue to accumulate even when cognitive function plateaus in AD patients, highlighting the advantages of PET in later disease stages. The differing relationships between cognition and tau deposition, and between gender, APOE4, and tau deposition, provide potential for subtype-specific treatments. Targeting gender-specific and genetic factors influencing tau deposition, as well as interventions aimed at tau's impact on cognition, may be effective.
阿尔茨海默病（AD）是一种异质性神经退行性疾病，其中tau神经原纤维缠结是与认知功能障碍和神经退行性变密切相关的病理标志。在本研究中，我们使用脑tau数据，通过识别和表征患者中的亚群来研究AD的异质性。我们纳入了615例认知正常者和159例AD患者的脑F-flortaucipr PET扫描数据，以及来自阿尔茨海默病神经影像倡议数据库的T1加权MRI数据。使用标准化摄取值比率（SUVR）图像，采用三维卷积神经网络模型进行AD检测。生成模型衍生的显著性图，并将其用作聚类AD参与者的信息性图像特征。在识别出的亚群中，比较了人口统计学、神经心理学测量和SUVR的统计分析。评估了神经心理学测量与区域SUVR之间的相关性。使用广义线性模型研究性别和APOE ε4对区域SUVR的交互作用。
揭示了两个不同的AD患者亚群，分别表示为S和S。与S组相比，S组大脑中的整体tau负担显著更高，但两组的认知分布水平相似。在S组中，神经心理学测量与区域tau沉积之间的关联减弱。此外，在S组中观察到性别和APOE ε4对tau沉积有显著的交互作用，但在S组中未发现这种作用。
我们的结果表明，如SUVR所示，即使AD患者的认知功能趋于平稳，tau缠结仍在继续积累，突出了PET在疾病后期阶段的优势。认知与tau沉积之间以及性别、APOE4与tau沉积之间的不同关系为亚型特异性治疗提供了潜力。针对影响tau沉积的性别特异性和遗传因素，以及针对tau对认知影响的干预措施可能是有效的。
