BACKGROUND Amyloid-β (Aβ) likely plays a primary role in Alzheimer's disease pathogenesis, but longitudinal Aβ, tau, and neurodegeneration (A/T/N) measurements in the same individuals have rarely been examined to verify the temporal dynamics of these biomarkers. METHODS In this study, we investigated the temporal ordering of Aβ, tau, and neurodegeneration using longitudinal biomarkers in nondemented elderly individuals. A total of 395 cognitively unimpaired individuals and 204 individuals with mild cognitive impairment (320 [53%] were female) were classified into 8 A±/T±/N± categories according to the abnormal (+)/normal (-) status of Aβ (18F-florbetapir or 18F-florbetaben) positron emission tomography (PET), 18F-flortaucipir PET, and adjusted hippocampal volume (aHCV). Follow-up Aβ PET, tau PET, and aHCV measurements at 0.6 to 4.1 years were available for 35% to 63% of the sample. Baseline Aβ, tau, and aHCV were compared between different A/T/N profiles. We investigated the associations of baseline and longitudinal Aβ, tau, and neurodegeneration in relation to one another continuously. RESULTS Among T- participants, tau was higher for A+/T-/N- individuals compared with the A-/T-/N- group (p = .02). Among N- participants, neurodegeneration was worse among A+/T+/N- individuals compared with the A-/T-/N- group (p = .001). High baseline Aβ was associated (p < .001) with subsequent tau increase and high baseline tau was associated (p = .002) with subsequent aHCV decrease, whereas high tau and low aHCV at baseline were not associated with subsequent Aβ increase. CONCLUSIONS These findings define a sequence of pathological events in Alzheimer's disease that support a current model of Alzheimer's disease pathogenesis in which Aβ appears early, followed by deposition of abnormal tau aggregates and subsequent neurodegeneration.

中文翻译：

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纵向认知和生物标志物测量支持阿尔茨海默病病理生理学中的单向通路

背景 β-淀粉样蛋白 (Aβ) 可能在阿尔茨海默氏病的发病机制中起主要作用，但很少检查同一个体的纵向 Aβ、tau 和神经变性 (A/T/N) 测量来验证这些生物标志物的时间动态。方法 在这项研究中，我们使用纵向生物标志物研究了非痴呆老年人中 Aβ、tau 和神经变性的时间顺序。共有 395 名认知未受损个体和 204 名轻度认知障碍个体（320 名 [53%] 为女性）根据异常（+）/正常（-）状态分为 8 个 A±/T±/N± 类别Aβ（18F-florbetapir 或 18F-florbetaben）正电子发射断层扫描 (PET)、18F-flortaucipir PET 和调整后的海马体积 (aHCV)。后续 Aβ PET、tau PET 和 aHCV 测量值为 0.6 至 4。35% 到 63% 的样本可以使用 1 年。在不同的 A/T/N 曲线之间比较基线 Aβ、tau 和 aHCV。我们连续调查了基线和纵向 Aβ、tau 和神经变性之间的关联。结果 在 T- 参与者中，与 A-/T-/N- 组相比，A+/T-/N- 个体的 tau 更高 (p = .02)。在 N- 参与者中，与 A-/T-/N- 组相比，A+/T+/N- 个体的神经变性更严重 (p = .001)。高基线 Aβ 与随后的 tau 增加相关 (p < .001)，高基线 tau 与随后的 aHCV 降低相关 (p = .002)，而基线时的高 tau 和低 aHCV 与随后的 Aβ 增加无关。结论 这些发现定义了阿尔茨海默病的一系列病理事件