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

项目摘要 海马体的CA 1子区域特别容易在衰老中发展tau病理， 临床前阿尔茨海默病（AD）。因此，CA 1的Tau相关功能障碍可能是 导致年龄和AD相关的记忆力下降。然而，以前没有研究调查过 CA 1中的tau病理学、CA 1激活和记忆性能之间的直接关系。新兴 有证据表明，CA 1支持统计学习，这是一种记忆过程， 不同的事件会快速学习和整合。统计学上CA 1激活与 学习和行为表现尚未在老年人群体中进行研究。在本研究中， 我们建议确定CA 1中的tau病理是否与CA 1激活功能障碍有关， 统计学习，以及这些因素是否有助于表达记忆障碍的认知 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蛋白， 用正电子发射断层扫描（PET）示踪剂[18F] MK-6240沉积和用任务- 基于fMRI，而受试者执行统计学习范式。我们利用现有的队列， NIH资助的PET生物标志物研究（PI：Yassa），在富含OAs的子样本中进行该辅助研究 淀粉样蛋白阳性（n=60，年龄60-85，60%女性）。在目标1中，我们将评估 统计学习性能和CA 1激活。我们假设高性能OA将具有 更大的CA 1激活比低性能OA，CA 1激活将增加整个任务， 刺激之间的相互作用是学习的。我们将进一步探讨统计学习的代表性， CA 1的前-后和远-近轴。在目标2中，我们将评估tau病理学对 CA 1激活和统计学习性能。我们假设海马tau蛋白病理学， CA 1 tau，将与统计学习上的激活降低和行为表现变差相关 任务我们将进一步开发方法来量化tau病理学，特别是在CA 1，利用 UCI PET扫描仪的无与伦比的分辨率。在目标3中，我们将使用静息状态功能连接来 确定内鼻-海马微电路如何随着tau病理改变。我们假设 海马tau蛋白与内嗅皮层和CA 1之间的连接性中断特别相关 （单突触通路）。我们还将探索CA 1和内嗅亚区之间的功能连接， 以及其他新皮层和皮层下区域。综上所述，拟议项目将首先评估 CA 1 tau病理学、CA 1功能和统计学学习行为表现之间的关系， 老化和临床前AD。这项研究的见解将有助于我们理解tau病理学如何 导致记忆力衰退和老年痴呆症。统计学习表现可能是一个有价值的行为 CA 1中潜在的tau病理学标志物，对评估降低tau治疗的试验具有意义。

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.