Dopaminergic mechanisms of resilience to Alzheimer's disease neuropathology

项目总结 而阿尔茨海默病(AD)相关的β-淀粉样蛋白(A-β)的发展与tau病理有关 随着种群水平上大脑结构和认知功能的下降，存在着相当大的异质性 在这些对个人的影响中。大脑多巴胺系统的个体差异代表着 令人信服的β和tau病理对大脑结构和功能的影响。之前的研究已经 一种“最佳”基因多态被认为可以增加多巴胺D2受体的亲和力 (DRD2 C957T；rs6277)与较大的皮质厚度相关。虽然驱动这种效应的机制 目前尚不清楚，多巴胺可以神经营养和D2受体介导的一些神经保护作用 可能抵消AD过程的功能，包括减少神经炎症。与 尽管有病理改变，但认知功能的成功维持与较高的D2受体可用性相关 有更好的执行功能和记忆力。我们认为DRD2 T/T基因支持对AD的抗逆性。 相关的tau和Aβ病理。分析将重点放在认知正常和轻度认知障碍群体上 其中，建立成功的AD复原力机制最为相关。我们将使用 阿尔茨海默病神经成像倡议(ADNI)数据集追求以下具体目标。我们将首先 建立DRD2T/T基因在β患者皮质增厚中的作用 ([18F]Florbetapir/Florbetaben)和tau([18F]Flortaucipir PET)横断面病理学(目标1)。接下来，我们将 探讨DRD2T/T基因在认知储备中的作用 临床前阿尔茨海默病患者执行功能和记忆的横断面和纵向测量 认知复合体。我们将检验T/T基因型与好于预期相关的假设 给予Tau和Aβ负担的认知(目标2)。最后，我们将使用临床应用程序跟踪纵向临床下降 痴呆量表-盒子的总和和皮质厚度的纵向下降，以确定 T/T基因型预示着较慢的临床衰退和脑维护(目标3)。圆满完成 这些目的将为多巴胺系统与AD病理相互作用影响衰老提供新的证据 轨迹，并将支持针对倾向于降低的个体的多巴胺系统的治疗靶点 D2亲和力。

PROJECT SUMMARY While the development of Alzheimer’s disease (AD)-related β-amyloid (Aβ) and tau pathology is associated with declines in brain structure and cognitive function on a population level, there is considerable heterogeneity in these effects across individuals. Individual differences in the brain’s dopamine system represent a compelling moderator of Aβ and tau pathology’s effects on brain structure and function. Previous research has established that an “optimal” genetic polymorphism presumed to increase dopamine D2 receptor affinity (DRD2 C957T; rs6277) is associated with greater cortical thickness. While the mechanisms driving this effect are not known, dopamine can be neurotrophic and D2 receptors mediate a number of neuroprotective functions that may counteract AD processes including reduction of neuroinflammation. Relevant to the successful maintenance of cognitive function despite pathology, higher D2 receptor availability is associated with better executive function and memory. We propose the DRD2 T/T genotype supports resilience to AD- related tau and Aβ pathology. Analyses will focus on cognitively normal and mild cognitive impairment groups for which establishing the mechanisms of successful AD resilience are most relevant. We will use the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset to pursue the following Specific Aims. We will first establish a role of the DRD2 T/T genotype in conferring greater cortical thickness despite Aβ ([18F]Florbetapir/Florbetaben) and tau ([18F]Flortaucipir PET) pathology cross-sectionally (Aim 1). Next, we will investigate the role of DRD2 T/T genotype in cognitive reserve by probing genotype x pathology interactions in cross-sectional and longitudinal measures of executive function and memory using the Preclinical Alzheimer Cognition Composite. We will test the hypothesis that the T/T genotype is associated with better-than-expected cognition given tau and Aβ burden (Aim 2). Finally, we will track longitudinal clinical decline using the Clinical Dementia Scale – Sum of Boxes and longitudinal decline in cortical thickness to determine the extent to which the T/T genotype predicts slower clinical decline and brain maintenance (Aim 3). The successful completion of these aims will provide novel evidence that the dopamine system interacts with AD pathology to affect aging trajectories, and will support therapeutic targeting of the dopamine system for individuals predisposed to lower D2 affinity.