Testing the role of tau pathology in disrupting hippocampal CA1 memory function in older adults at risk for Alzheimer’s disease

项目总结 海马区CA1亚区特别容易发生tau病理 临床前阿尔茨海默病(AD)。因此，与tau相关的CA1功能障碍可能是 会导致与年龄和AD相关的记忆力下降。然而，之前没有任何研究调查过 CA1中tau的病理变化、CA1的激活和记忆能力之间存在直接关系。新兴 证据表明，CA1支持统计学习，这是一种记忆过程，在这种记忆过程中， 不同的情节正在迅速学习和整合。CA1在统计过程中的激活关系 学习和行为表现还没有在老年人群中进行调查。在这项研究中， 我们建议确定CA1中tau的病理是否与CA1功能障碍的激活有关 统计学习，以及这些因素是否有助于认知能力中记忆障碍的表达 正常老年人(OA)。我们将使用一种新的高分辨率多模式神经成像设计，评估tau 用正电子发射断层扫描(PET)示踪剂[18F]MK-6240沉积和激活CA1任务- 基于功能磁共振成像，而受试者执行统计学习范式。我们利用现有的队列来自 美国国立卫生研究院资助的PET生物标记物研究(PI：YASSA)在OAS富集子样本中进行这项辅助研究 淀粉样蛋白阳性(n=60，年龄60-85岁，女性占60%)。在目标1中，我们将评估 骨性关节炎患者的统计学习成绩和CA1激活。我们假设高性能的办公自动化将会有 CA1激活比低执行的OA更大，且CA1的激活将在整个任务中增加 刺激之间的规律性是可以学习的。我们将进一步探索统计学习的表示形式 CA1的前-后轴和远近侧轴。在目标2中，我们将评估tau病理对 CA1激活和统计学习成绩。我们假设海马tau的病理，反映了 CA1 tau，将与激活减少和在统计学习上的行为表现较差有关 任务。我们将进一步开发量化tau病理的方法，特别是在CA1内，利用 UCI的PET扫描仪具有无与伦比的分辨率。在目标3中，我们将使用静息状态功能连接来 确定tau病理如何改变内嗅觉-海马区微回路。我们假设 海马tau将与内嗅皮层和CA1之间的连接中断特别相关。 (单突触途径)。我们还将探索CA1和内嗅亚区之间的功能连接， 以及其他新皮质和皮质下区域。总之，拟议的项目将是第一个评估 CA1-tau病理、CA1功能与统计学习行为成绩的关系 衰老与临床前阿尔茨海默病这项研究的见解将有助于我们理解tau的病理机制 导致衰老和阿尔茨海默病的记忆衰退。统计学习成绩可能是一种有价值的行为 CA1潜在tau病理的标记物，以及对评估降低tau疗法的试验的影响。

PROJECT SUMMARY The CA1 subfield of the hippocampus is particularly susceptible to developing tau pathology in aging and preclinical Alzheimer’s disease (AD). Tau-related dysfunction of CA1 is therefore a likely candidate to contribute to both age- and AD-related memory decline. However, no previous study has investigated the direct relationship between tau pathology in CA1, CA1 activation, and memory performance. Emerging evidence suggests that CA1 supports statistical learning, a memory process in which regularities between distinct episodes are rapidly learning and integrated. The relationship between CA1 activation during statistical learning and behavioral performance has not yet been investigated in an older adult population. In this study, we propose to determine whether tau pathology in CA1 is associated with dysfunctional CA1 activation during statistical learning, and whether these factors contribute to the expression of memory impairment in cognitive normal older adults (OA). We will use a novel high-resolution multimodal neuroimaging design, assessing tau deposition with the positron emission tomography (PET) tracer [18F] MK-6240 and CA1 activation with task- based fMRI while subjects perform a statistical learning paradigm. We leverage an existing cohort from an NIH-funded PET biomarker study (PI: Yassa) to conduct this ancillary study in a subsample of OAs enriched for amyloid-positivity (n=60, age 60-85, 60% women). In Aim 1, we will assess the relationship between statistical learning performance and CA1 activation in OA. We hypothesize that high-performing OA will have greater CA1 activation than low-performing OA, and that CA1 activation will increase across the task as regularities between stimuli are learned. We will further explore the representation of statistical learning across the anterior-posterior and distal-proximal axes of CA1. In Aim 2, we will assess the impact of tau pathology on CA1 activation and statistical learning performance. We hypothesize that hippocampal tau pathology, reflecting CA1 tau, will be related to decreased activation and worse behavioral performance on the statistical learning task. We will further develop methods to quantify tau pathology specifically within CA1, leveraging the unmatched resolution of UCI’s PET scanner. In Aim 3, we will use resting state functional connectivity to identify how entorhinal-hippocampal microcircuits are altered with tau pathology. We hypothesize that hippocampal tau will specifically be related to disrupted connectivity between the entorhinal cortex and CA1 (monosynaptic pathway). We will also explore functional connectivity between CA1 and entorhinal subregions, and other neocortical and subcortical regions. In summary, the proposed project will be the first to assess relationships between CA1 tau pathology, CA1 function, and statistical learning behavioral performance in aging and preclinical AD. Insights from this study will contribute to our understanding of how tau pathology leads to memory decline in aging and AD. Statistical learning performance may be a valuable behavioral marker of underlying tau pathology in CA1, with implications for trials assessing tau-lowering therapeutics.