Abstract

Purpose

Alzheimer’s disease (AD) is characterised by two cardinal pathologies, namely the extracellular accumulation amyloid-related aggregates, and the intracellular formation of tau-related neurofibrillary tangles (NFTs). While both pathologies disrupt cognitive function, a large body of evidence suggests that tau-pathology has a stronger relationship with the clinical manifestation of the disease compared to amyloid. Given the ordinal nature of histopathological staging systems, however, it is possible that the effect of amyloid pathology has been underestimated in clinicopathological studies.

Methods

We investigated this possibility using data from the National Alzheimer’s Coordinating Center (NACC) database, which contains data from patients in the United States of America. Bayesian ordinal models were used to directly investigate the relative contribution of Braak NFT, diffuse plaque, and neuritic plaque staging to the severity of antemortem clinical impairment.

Results

Data from 144 participants were included in the final analysis. Bayesian ordinal models revealed that Braak NFT stage was the only predictor of global cognitive status, clinical dementia stage, functional abilities, and neuropsychiatric symptoms. When compared directly, Braak NFT stage was a stronger predictor than diffuse or neuritic plaques across these domains.

Conclusions

These findings confirm that tau-related pathology is more strongly related to clinical status than amyloid pathology. This suggests that conventional clinical markers of disease progression might be insensitive to amyloid-pathology, and hence might be inappropriate for use as outcome measures in therapeutic trials that directly target amyloid.

中文翻译：

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tau 而非淀粉样蛋白的组织病理学分期对应于生前认知状态、痴呆阶段、功能能力和神经精神症状

摘要

目的

阿尔茨海默病 (AD) 的特征在于两种主要病理，即细胞外淀粉样蛋白相关聚集体和 tau 相关神经原纤维缠结 (NFT) 的细胞内形成。虽然这两种病理都会破坏认知功能，但大量证据表明，与淀粉样蛋白相比，tau 病理与疾病的临床表现有更强的关系。然而，鉴于组织病理学分期系统的顺序性质，临床病理学研究中可能低估了淀粉样蛋白病理学的影响。

方法

我们使用来自美国国家阿尔茨海默病协调中心 (NACC) 数据库的数据调查了这种可能性，该数据库包含来自美国患者的数据。贝叶斯序数模型用于直接研究 Braak NFT、弥漫性斑块和神经炎斑块分期对死前临床损伤严重程度的相对贡献。

结果

来自 144 名参与者的数据被纳入最终分析。贝叶斯序数模型显示，Braak NFT 分期是整体认知状态、临床痴呆分期、功能能力和神经精神症状的唯一预测因子​​。直接比较时，Braak NFT 分期是比这些域中的弥漫性或神经炎斑块更强的预测因子。

结论

这些发现证实，与淀粉样蛋白病理相比，tau 相关病理与临床状态的相关性更强。这表明疾病进展的常规临床标志物可能对淀粉样蛋白病理学不敏感，因此可能不适合用作直接针对淀粉样蛋白的治疗试验中的结果测量。