This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.

中文翻译：

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淀粉样蛋白和 tau 成像生物标志物解释了中年后期的认知衰退。

这项研究调查了从威斯康星州阿尔茨海默病预防登记处抽样的最初认知未受损的参与者中淀粉样蛋白和 tau PET 生物标志物分层组之间回顾性认知轨迹的差异。根据 11C-匹兹堡化合物 B (PiB) 和 18F-MK-6240 PET 成像，167 名最初未受损的个体（基线年龄 59 ± 6 岁；115 名女性）根据升高的淀粉样蛋白-β 和 tau 状态进行分层。混合效应模型用于确定基于包括记忆和执行功能在内的认知测试组合的纵向认知轨迹是否在生物标志物组之间存在差异。二级分析调查了各种横断面健康和认知测试的组别差异，以及 18F-MK-6240、11C-PiB 和年龄之间的关联。通过事后比较观察到显着的组别×年龄相互作用，表明淀粉样蛋白和 tau 病理生理学均升高的组与仅具有一种或没有升高的生物标志物的组相比，在回顾性认知中的下降速度大约快三倍。这一结果对于定义升高的 tau 的各种阈值和内侧颞叶区域是稳健的。参与者相对健康，并且在研究开始或结束时的健康因素生物标志物组之间或研究开始时的大多数认知测量方面大多没有差异。调查年龄、MK-6240 和 PiB 之间关联的分析表明，缠结相关区域中年龄和 18F-MK-6240 之间的关联较弱，在调整 11C-PiB 后可以忽略不计。强烈的联系，特别是在内嗅皮质、海马体和杏仁核中，在 18F-MK-6240 和全球 11C-PiB 之间观察到与 Braak 神经原纤维缠结阶段 I-VI 相关的区域。这些结果表明，病理性淀粉样蛋白和 tau 的结合不利于中年晚期临床前阿尔茨海默病的认知能力下降。在阿尔茨海默病连续体中，中年健康因素可能不会对临床前认知能力下降产生很大影响。未来需要在更大的临床前样本中进行研究，以确定淀粉样蛋白和 tau 蛋白的个体贡献是否以及在何种程度上影响认知能力下降。18F-MK-6240 有望成为检测临床前阿尔茨海默病神经原纤维缠结的敏感生物标志物。这些结果表明，病理性淀粉样蛋白和 tau 的结合不利于中年晚期临床前阿尔茨海默病的认知能力下降。在阿尔茨海默病连续体中，中年健康因素可能不会对临床前认知能力下降产生很大影响。未来需要在更大的临床前样本中进行研究，以确定淀粉样蛋白和 tau 蛋白的个体贡献是否以及在何种程度上影响认知能力下降。18F-MK-6240 有望成为检测临床前阿尔茨海默病神经原纤维缠结的敏感生物标志物。这些结果表明，病理性淀粉样蛋白和 tau 的结合不利于中年晚期临床前阿尔茨海默病的认知能力下降。在阿尔茨海默病连续体中，中年健康因素可能不会对临床前认知能力下降产生很大影响。未来需要在更大的临床前样本中进行研究，以确定淀粉样蛋白和 tau 蛋白的个体贡献是否以及在何种程度上影响认知能力下降。18F-MK-6240 有望成为检测临床前阿尔茨海默病神经原纤维缠结的敏感生物标志物。中年健康因素可能不会对临床前认知能力下降产生很大影响。未来需要在更大的临床前样本中进行研究，以确定淀粉样蛋白和 tau 蛋白的个体贡献是否以及在何种程度上影响认知能力下降。18F-MK-6240 有望成为检测临床前阿尔茨海默病神经原纤维缠结的敏感生物标志物。中年健康因素可能不会对临床前认知能力下降产生很大影响。未来需要在更大的临床前样本中进行研究，以确定淀粉样蛋白和 tau 蛋白的个体贡献是否以及在何种程度上影响认知能力下降。18F-MK-6240 有望成为检测临床前阿尔茨海默病神经原纤维缠结的敏感生物标志物。