Department of Radiology, Brain Health Imaging Institute, Weill Cornell Medicine, New York, NY, USA.
Department of Radiology, Weill Cornell Medicine, New York, NY, USA.
J Alzheimers Dis. 2024;98(4):1467-1482. doi: 10.3233/JAD-231362.
Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-β (Aβ) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear.
In this study, we utilized Aβ and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aβ deposition.
Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aβ associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration.
No significant tau-Aβ association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aβ in lateral temporal lobe regions. The strongest tau-Aβ associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aβ (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aβ associations were no longer significant.
The results indicate that associations between tau and Aβ are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD.
阿尔茨海默病（AD）的组织病理学研究表明，细胞外淀粉样β（Aβ）斑块促进神经原纤维缠结的tau 蛋白扩散。然而，这两种蛋白病变起始于空间上不同的脑区，因此在 AD 进展过程中它们如何相互作用尚不清楚。
在这项研究中，我们利用来自 572 名老年受试者（476 名健康对照组（HC）、14 名轻度认知障碍（MCI）、82 名轻度 AD）的 Aβ和 tau 正电子发射断层扫描（PET）扫描，在疾病的不同阶段，研究 tau 与皮质 Aβ沉积的关联程度。
我们使用多元线性回归模型和伪纵向排序技术，根据 tau 的扩散，在 AD 进展的四个病理阶段（1）无 tau 阶段、2）加速前期、3）加速阶段和 4）加速后期，研究 tau 与皮质 Aβ的远程关联。
在无 tau 阶段未发现 tau-Aβ 显著关联。在 tau 沉积的最早阶段——加速前期，内侧颞叶（MTL）（即，内嗅皮层、海马旁回）的区域性 tau 与外侧颞叶区域的皮质 Aβ之间出现了关联。在加速阶段，tau 在 MTL 区域与皮质 Aβ（即颞叶和额叶区域）的关联最强。引人注目的是，在加速后期，包括 96%的有症状受试者，tau-Aβ 关联不再显著。
结果表明，tau 与 Aβ 之间的关联是阶段性的，这对理解 AD 进展过程中这两种蛋白病变之间的相互作用具有重要意义。
