Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, SE-222 42 Lund, Sweden.
German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany.
Brain. 2023 Aug 1;146(8):3192-3205. doi: 10.1093/brain/awad135.
Amyloid-β (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aβ, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aβ-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aβ in vivo. Immunohistochemistry was used to estimate Aβ load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aβ. This was also observed in individuals with low Aβ load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aβ. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aβ pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aβ-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aβ-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aβ density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aβ pathology.
淀粉样蛋白-β（Aβ）被假设为促进tau 病理学在海马体以外的传播。然而，有证据表明，独立于 Aβ，年龄相关的 tau 病理学可能存在于海马体以外。因此，我们旨在研究两个大型队列中海马体以外与年龄相关的 Aβ 无关的 tau 沉积，并研究其对认知和结构测量的潜在下游影响。我们纳入了来自 BioFINDER-2 研究（体内）的 545 名认知正常的成年人（40-92 岁）和来自 Rush 阿尔茨海默病中心队列的 639 名（64-108 岁）（体外）。通过 18F-RO948 和 18F-flutemetamol-PET 标准化摄取比值计算体内区域 tau 和全局/区域 Aβ。免疫组化用于体外估计 Aβ 负荷和缠结密度。使用 Hippocampal Subfields 自动分割包获得体内海马体（下托、角回 1）体积和皮质厚度（内嗅皮质、Brodmann 区域 35）。使用 FreeSurfer 确定早发性和晚发性新皮质阿尔茨海默病区域的厚度。使用全球认知和情景记忆来估计认知功能。体内与年龄相关的 tau 沉积在海马体以及额顶皮质区域中被观察到，在调整 Aβ 后具有统计学意义。在低 Aβ 负荷的个体中也观察到了这一点。tau 沉积与颞叶和顶叶区域的皮质体积和厚度呈负相关，独立于 Aβ。在具有早期阿尔茨海默病病理学的区域中，tau 沉积与皮质体积或厚度之间的关联部分通过皮质中介，即早期 tau 和/或 Aβ 病理学（下托/Brodmann 区域 35/楔前叶/后扣带回）。最后，即使包括 Aβ-PET 作为协变量，tau 也部分介导了年龄和认知之间的关联在 Brodmann 区域 35 中。结果在体外队列中得到验证，显示了海马体内外与年龄相关且与 Aβ 无关的 tau 聚集物的增加。体外年龄认知关联由内侧和下颞叶 tau 缠结密度介导，同时校正 Aβ 密度。总之，我们的研究为体内和体外与年龄相关的 tau 病提供了支持，即使在海马体以外也是如此，对结构和认知有下游影响。这些结果对我们理解 tau 在海马体以外的传播具有启示意义，在阿尔茨海默病的背景下也是如此。此外，这项研究表明，tau 靶向治疗在与年龄相关的原发性 tau 病中可能具有潜在的效用，可能在低 Aβ 病理个体中已经处于临床前阶段。
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