The temporal evolutions and relative orderings of Alzheimer disease biomarkers, including CSF amyloid-β42 (Aβ42), Aβ40, total tau (Tau) and phosphorylated tau181 (pTau181), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar amyloid-β with PET using the 11C-Pittsburgh Compound-B (PiB), MRI-based hippocampal volume and cortical thickness and cognition have been hypothesized but not yet fully tested with longitudinal data for all major biomarker modalities among cognitively normal individuals across the adult lifespan starting from 18 years. By leveraging a large harmonized database from 8 biomarker studies with longitudinal data from 2609 participants in cognition, 873 in MRI biomarkers, 519 in PET PiB imaging and 475 in CSF biomarkers for a median follow-up of 5-6 years, we estimated the longitudinal trajectories of all major Alzheimer disease biomarkers as functions of baseline age that spanned from 18 to 103 years, located the baseline age window at which the longitudinal rates of change accelerated and further examined possible modifying effects of apolipoprotein E (APOE) genotype. We observed that participants 18-45 years at baseline exhibited learning effects on cognition and unexpected directions of change on CSF and PiB biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aβ42 and Aβ42/Aβ40 ratio (with an increase) and for Tau, and pTau181 (with a decrease) at the next baseline age interval of 45-50 years, followed by an accelerated increase for PiB SUVR at the baseline age of 50-55 years and an accelerated decrease for hippocampal volume at the baseline age of 55-60 years and finally by an accelerated decline for cortical thickness and cognition at the baseline age of 65-70 years. Another acceleration in the rate of change occurred at the baseline age of 65-70 years for Aβ42/Aβ40 ratio, Tau, pTau181, PiB SUVR and hippocampal volume. Accelerated declines in hippocampal volume and cognition continued after 70 years. For participants 18-45 years at baseline, significant increases in Aβ42 and Aβ42/Aβ40 ratio and decreases in PiB SUVR occurred in APOE ɛ4 non-carriers but not carriers. After age 45 years, APOE ɛ4 carriers had greater magnitudes than non-carriers in the rates of change for all CSF biomarkers, PiB SUVR and cognition. Our results characterize the temporal evolutions and relative orderings of Alzheimer disease biomarkers across the adult lifespan and the modification effect of APOE ɛ4. These findings may better inform the design of prevention trials on Alzheimer disease.

中文翻译：

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阿尔茨海默病生物标志物在整个成人生命周期中的加速纵向变化和排序。

阿尔茨海默病生物标志物的时间演变和相对顺序，包括脑脊液淀粉样蛋白-β42 (Aβ42)、Aβ40、总 tau (Tau) 和磷酸化 tau181 (pTau181)、脑纤维淀粉样蛋白分子成像的标准化摄取值比 (SUVR)使用 11C-匹兹堡化合物-B (PiB) 进行 PET 扫描，基于 MRI 的海马体积、皮质厚度和认知能力已被假设，但尚未使用成年生命周期中认知正常个体中所有主要生物标志物模式的纵向数据进行充分测试从 18 岁开始。通过利用 8 项生物标志物研究的大型统一数据库，以及来自 2609 名认知参与者、873 名 MRI 生物标志物参与者、519 名 PET PiB 成像参与者和 475 名脑脊液生物标志物参与者的纵向数据，中位随访时间为 5-6 年，我们估计了纵向数据所有主要阿尔茨海默病生物标志物的轨迹作为跨度为 18 至 103 岁的基线年龄的函数，定位了纵向变化率加速的基线年龄窗口，并进一步检查了载脂蛋白 E (APOE) 基因型可能的修饰作用。我们观察到，基线时 18-45 岁的参与者表现出对认知的学习效果以及 CSF 和 PiB 生物标志物的意外变化方向。CSF Aβ42 和 Aβ42/Aβ40 比率（增加）以及 Tau 和 pTau181（减少）的纵向变化最早出现在下一个基线年龄间隔 45-50 岁，随后 PiB 加速增加基线年龄为 50-55 岁时出现 SUVR，基线年龄为 55-60 岁时海马体积加速下降，最后在 65-70 岁基线年龄时皮质厚度和认知能力加速下降。Aβ42/Aβ40 比率、Tau、pTau181、PiB SUVR 和海马体积的变化率另一个加速发生在 65-70 岁的基线年龄。70 年后，海马体积和认知能力继续加速下降。对于基线时 18-45 岁的参与者，APOE ɛ4 非携带者而非携带者中 Aβ42 和 Aβ42/Aβ40 比率显着增加，PiB SUVR 下降。45 岁后，APOE ɛ4 携带者在所有 CSF 生物标志物、PiB SUVR 和认知的变化率方面比非携带者具有更大的幅度。我们的结果描述了阿尔茨海默病生物标志物在整个成人寿命中的时间演变和相对排序以及 APOE ɛ4 的修饰效应。这些发现可能会更好地为阿尔茨海默病预防试验的设计提供信息。