A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic ¹⁸F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline ¹⁸F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer’s disease could be illustrated with biomarker measurement under NIA–AA framework. Clinical–neuroimaging–neuropathological studies in other cohorts are needed to validate these findings.

国家老龄化研究所-阿尔茨海默氏症协会 (NIA-AA) 提出了一个用二分法生物标志物测量来定义阿尔茨海默病的生物学研究框架。然而，它不能表征 tau 病理学的层次传播模式。为了使用生物标志物反映体内 tau 进展，我们构建了具有纵向临床验证的精细地形¹⁸ F-AV-1451 tau PET 分期方案。^基线18的 734 名参与者F-AV-1451 tau PET（基线年龄 73.9 ± 7.7 岁，375 名女性）通过地形 PET 分期方案分为五个阶段。使用线性混合效应模型和 Cox 比例风险模型，在有或没有淀粉样蛋白状态进一步二分法的情况下跨阶段比较认知轨迹和临床进展。在第 1 阶段首次观察到显着的认知能力下降，当时 tau 水平仅在经鼻区域增加。从第 2 阶段到第 3 阶段和第 4 阶段，认知能力下降和临床进展的速度加快。较高的阶段还与较高的 CSF 磷酸化 tau 和第 1 阶段的总 tau 浓度相关。在新皮质区域正常 β-淀粉样蛋白没有出现异常 tau 积累但通过与颞区的 β-淀粉样蛋白相互作用会导致认知能力下降。颞区高度积累的 tau 独立导致认知恶化。地形PET分期方案在早期诊断、预测疾病进展和研究疾病机制方面具有潜力。阿尔茨海默病中的特征性 tau 扩散模式可以通过 NIA-AA 框架下的生物标志物测量来说明。需要在其他队列中进行临床-神经影像学-神经病理学研究来验证这些发现。